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Cancer without Disease
Abstract
Do inhibitors of blood-vessel growth found naturally in our bodies defend most of us against progression of cancer to a lethal stage?
... Multicellular organisms are generally composed of normal cooperating cells, but can also harbor host cells that proliferate abnormally and form masses called tumors or neoplasms [1]. Tumors are usually classified into two main categories: benign or malignant. ...
... sim1<-glmmTMB(bud_type~Phase*Status+(1|ID_parent),REML = TRUE, family=binomial(logit),data = all) sim2<-glmmTMB(bud_type~Phase*Status+(1|Parent_birthday),REML = TRUE, family=binomial(logit),d ata = all) sim3<-glmmTMB(bud_type~Phase*Status+(1|ID_parent)+(1|Parent_birthday),REML = TRUE, family=bin omial(logit),data = all) sim4<-glmmTMB(bud_type~Phase*Status,REML = TRUE, family=binomial(logit),data = all) ## model weights ## [1] 0.489 0.511 ...
... surv1<-glmmTMB(Survival~Status*Production_phase*Bud_type+(1|Complet_batch)+(1|Survey_date),RE ML=TRUE, family = binomial(logit),data=transmission) surv2<-glmmTMB(Survival~Status*Production_phase*Bud_type+(1|Complet_batch),REML=TRUE, family = binomial(logit),data=transmission) surv3<-glmmTMB(Survival~Status*Production_phase*Bud_type+(1|Survey_date),REML=TRUE, family = binomial(logit),data=transmission) surv4<-glmmTMB(Survival~Status*Production_phase*Bud_type+(1|Survey_date/Complet_batch),REML=T RUE, family = binomial(logit),data=transmission) surv5<-glmmTMB(Survival~Status*Production_phase*Bud_type,REML=TRUE, family = binomial(logit), data=transmission) ## model weights ## [1] 0.387 0.226 0.000 0.387 0.000 ...
Tumors form as a result of abnormal and uncontrolled proliferation of cells within a multicellular organism, which can lead to cancer. Although this phenomenon exists in all metazoans, most research has focused on malignancies in humans and domestic animals. Thus, the evolutionary ecology of host-tumor interactions and their consequences for ecosystem functioning is a virtually untouched area of research.
To address these scientific questions, the biological model used in this thesis is a freshwater cnidarian, the brown hydra hydra oligactis, some of whose laboratory lines harbor tumors with notable specificities. In addition to the fact that the benign/malignant status of these tumors is not clear, they are capable of vertical transmission, during asexual reproduction of their host by budding. Furthermore, tumorous hydras have an increased number of tentacles compared to healthy hydras.
This thesis is organized in 5 sections, an introduction with two synthesis articles, three chapters presenting the research done and a general discussion. The first synthesis deals with the comparison between benign and malignant tumors, the second one deals with the costs of anticancer defenses in host organisms.
Our research on H. oligactis first described spontaneous tumors within several wild-type lineages (Chapter 1). This work shows that brown hydra tumors always appear to be of germline origin.
Moreover, we show that the presence of a bacterial species of the order Chlamydiales, could play a role in the initiation and/or maintenance of these tumor processes.
We then studied (chapter 2) the impact of the tumor-bacterial transmissible complex (i.e. tumor cells and bacteria) on the life history traits of the hydra host. This work shows that polyps derived from tumorous parents, prior to becoming tumoral themselves, intensify their sexual and asexual reproductive e�orts. Moreover, these tumorous polyps subsequently have a reduced survival compared to healthy ones. The adaptive nature of these life history trait changes, for the host and/or for the transmissible tumor cells, is discussed. This chapter also focuses on the origin of the increased number of tentacles in tumor polyps. By transplanting di�erent tumors into hydras of varying genetic background, we showed that polyps developing supernumerary tentacles after transplantation were always those that had received tumor tissue from hydras lines harboring transmissible tumors, and already associated with the appearance of supernumerary tentacles in their original host. Rather than a compensatory response initiated by the host, the growth of supernumerary tentacles in some tumor-bearing hydras would therefore be induced by transmissible
tumor cells.
Finally, in order to improve our understanding of the ecological consequences of host-tumor interactions on ecosystem functioning, we experimentally explored (Chapter 3) the relationships that tumor-bearing hydras have with other animal species living in aquatic environments. We demonstrated that, compared to healthy hydras, tumorous ones had an increased risk of predation by fish, a higher rate of colonization by commensal ciliates, and their ability to capture prey was superior due to their increased number of tentacles.
Taken together, this work argues for a better consideration of tumor processes in evolutionary ecology, both in terms of the ecological and evolutionary trajectory of host species and the consequences of these interactions on ecosystem functioning.
... For disease to occur, cellular changes must happen continuously over a long period of time (usually several years). 23 Although cancer is usually associated with adults, it is also a leading cause of death among children and adolescents worldwide. The most common types of childhood cancer are leukemia, tumors of the central nervous system (brain and spinal cord), lymphoma and various types of solid tumors, neuroblastoma being the most common of the latter. ...
... So, the solution (0, 0,Ṽ ) is unstable. On the dynamics and optimal control of a mathematical model of neuroblastoma and its treatment -Insights from a mathematical model" 23 Proof. For C 0 = 0, the following impulsive system is obtained dI dt = β 3 IV − σ 1 I, nT ≤ t < (n + 1)T, ...
Celyvir is an advanced therapy medicine, consisting of mesenchymal stem cells (MSCs) containing the oncolytic virus ICOVIR 5. This paper sets out a dynamic system which attempts to capture the fundamental relationships between cancer, the immune system and adenoviruses. Two forms of treatment were studied: continuous and periodic, the second being closer to the real situation. In the analysis of the first model, in addition to identifying the critical points, their properties and bifurcation points, a number of numerical simulations were carried out. It has thus been shown that there are bistability regimes in which Celyvir can produce an equilibrium of tumor progression, or even freedom from tumor. A sensitivity analysis was also performed to determine which parameters are most important in the system. Subsequently, an optimal control problem with nonlinear objective functional has been formulated, where the therapeutic goal is not only to minimize the size of the tumor cell population and the total cost of treatment, but also to prevent the tumor from reaching a critical size. It has been shown that the optimal control is bang–bang. With the second model, a threshold value of viral load has been identified at which the success of the treatment could be ensured. It is clear in both models that a low viral load would lead to relapse of the disease. Finally, it is shown that a periodic bang–bang regime should be used to optimize treatment with Celyvir.
... 8 En mi caso, padecí de estrés emocional y después de muchas "pérdidas", apareció mi enfermedad física: "Carcinoma ductal infiltrante" estadio I en mi mama izquierda. 9 El doctor Herbert Benson, cardiólogo de la Universidad de Harvard, fue un pionero en determinar la relación entre diferentes grados de estímulos estresantes y enfermedades como la hipertensión arterial. En su libro < Relaxation Response> (Respuesta de Relajación) 10 presenta una escala de impacto de acuerdo al tipo de estrés. ...
El estrés crónico tiene un impacto profundo en el cuerpo, afectando diversos sistemas, incluyendo el inmunológico. El eje hipotálamo-pituitario-suprarrenal (HPA) regula la respuesta al estrés, liberando cortisol y adrenalina que, si son elevados durante períodos prolongados, pueden desencadenar enfermedades. La doctora Candice Pert descubrió que los neuro-péptidos, son moléculas que conectan el cerebro con el cuerpo, desempeñan un papel crucial en cómo las emociones influyen en la salud. Las emociones reprimidas, como la tristeza, rabia y miedo, alteran esta red molecular, debilitando el sistema inmunológico y favoreciendo la inflamación crónica, un factor importante en el cáncer. Además, estudios del Dr. Herbert Benson muestran cómo las “pérdidas” emocionales elevan el estrés y aumentan el riesgo de enfermedad. Las terapias como la psicoterapia, la musicoterapia y la hidroterapia pueden ser útiles en la sanación emocional y física. La salud intestinal es fundamental para el bienestar general, como lo señalaba Hipócrates. El microbiota, compuesta por bacterias, hongos, virus y parásitos, actúa como un órgano vital que influye en el sistema inmunológico, la producción de hormonas y neurotransmisores, y el metabolismo. Mantener un equilibrio entre los microbios intestinales es esencial para prevenir enfermedades, incluidas las crónicas. Una disbiosis, o desequilibrio del microbiota, puede generar inflamación crónica, afectando sistemas vitales y propiciando enfermedades autoinmunes, diabetes, enfermedades cardiovasculares y Cáncer. Una dieta basada en alimentos derivados de las plantas, ricos en fibra es esencial para la salud intestinal y la función del microbiota. Las fibras solubles (prebióticos) alimentan a las bacterias beneficiosas (firmicutes, bacteriodetes y otras) y el resultado de su trabajo son los post-bióticos como los butiratos, ácidos grasos de cadena corta, fundamentales para la salud del colon y el cerebro. Estos compuestos no solo nutren las células intestinales, sino que también refuerzan la barrera intestinal, previenen la pérdida de memoria y ayudan a mantener un peso corporal saludable. Otros ayudantes para la salud del intestino son los alimentos fermentados, como el yogurt, kefir, y kimchi, proporcionan probióticos que apoyan la diversidad bacteriana intestinal. El Dr. Will Bulsiewicz enfatiza que la fibra es el “corazón” de la salud intestinal, ayudando a prevenir enfermedades inflamatorias y crónicas al mantener un equilibrio entre los diferentes tipos de bacterias intestinales. Además, la conexión entre el intestino y el cerebro resalta la importancia de una alimentación adecuada para mejorar el estado de ánimo, reducir la ansiedad y mantener la salud mental y física. En síntesis, la salud es el resultado de un equilibrio entre el cuerpo, la mente y la alimentación. Mantener un microbiota intestinal saludable, gestionar el estrés y consumir una dieta rica en fibra y probióticos son fundamentales para prevenir y tratar enfermedades, incluyendo el cáncer. Las fuerzas naturales, como el sueño, la actividad física, las terapias emocionales y el factor fe complementan estos esfuerzos y permiten una sanación integral.
... In the early 1970s, Folkman demonstrated that growth of initiating tumor microfoci was limited by the distance oxygen could diffuse from the nearest capillary blood vessel (<250 micrometers) [47,48]. Indeed, most melanocytic neoplasms and tumor microfoci arrest at a dormant stage and are harmless unless they recruit new capillaries carrying oxygen and nutrients required for growth [49]. Transition from benign to cancerous growth depends on crucial support from the ECM and neoangiogenesis, which provides the early growth with space and nutrients while connecting the tumor to the circulatory system [43][44][45]. ...
Clinical melanoma identification relies on subjective visual criteria like color, shape, and size. Current imaging technologies rely on similar parameters without insight into underlying biological changes, necessitating invasive diagnostic approaches. Diagnosing lesions that fall into the “grey area,” neither clearly melanoma nor benign/common nevi, presents a particular challenge. Stromal tissue remodeling, pivotal in the early stages of malignancy, is intricately linked to integrins, with αvβ3 integrin playing a prominent role and facilitating neoangiogenesis. For this reason, in vivo molecular skin fluorescent imaging (mSFI) is a promising solution, providing molecular insights at the point of care for improved patient management. This chapter delves into melanoma development and detection, focusing on the molecular processes in melanocytic lesion transition to malignancy. In vivo fluorescence imaging, such as mSFI, can help dermatologists make strategic biopsy decisions by revealing integrin expression in remodeled stroma, shedding light on oncogenic processes.
... Not only are neoplastic processes ubiquitous in metazoans, but they are also present, sooner or later, in the bodies of all individuals of these species . They may be more or less abundant, more or less aggressive (the most serious form is metastatic cancer, which is usually fatal, Dillekås, Rogers, and Straume 2019), but in all cases, they are omnipresent (Folkman and Kalluri 2004;Maley et al. 2017). Moreover, when neoplasia progresses to a malignant invasive tumour (i.e. ...
While it is recognised that most, if not all, multicellular organisms harbour neoplastic processes within their bodies, the timing of when these undesirable cell proliferations are most likely to occur and progress throughout the organism's lifetime remains only partially documented. Due to the different mechanisms implicated in tumourigenesis, it is highly unlikely that this probability remains constant at all times and stages of life. In this article, we summarise what is known about this variation, considering the roles of age, season and circadian rhythm. While most studies requiring that level of detail be done on humans, we also review available evidence in other animal species. For each of these timescales, we identify mechanisms or biological functions shaping the variation. When possible, we show that evolutionary processes likely played a role, either directly to regulate the cancer risk or indirectly through trade‐offs. We find that neoplastic risk varies with age in a more complex way than predicted by early epidemiological models: rather than resulting from mutations alone, tumour development is dictated by tissue‐ and age‐specific processes. Similarly, the seasonal cycle can be associated with risk variation in some species with life‐history events such as sexual competition or mating being timed according to the season. Lastly, we show that the circadian cycle influences tumourigenesis in physiological, pathological and therapeutic contexts. We also highlight two biological functions at the core of these variations across our three timescales: immunity and metabolism. Finally, we show that our understanding of the entanglement between tumourigenic processes and biological cycles is constrained by the limited number of species for which we have extensive data. Improving our knowledge of the periods of vulnerability to the onset and/or progression of (malignant) tumours is a key issue that deserves further investigation, as it is key to successful cancer prevention strategies.
... The bulk of these tumors may be stopped by our body from drawing in fresh blood, preventing their potential growth caused by a deficiency in nutrients and oxygen. So, an in-situ tumor can stay latent indefinitely if there is no angiogenesis which is the growth of new blood vessels [75]. Environmental exposures rather than genetic predispositions were the primary cause of the majority of cancers [76]. ...
Plants are being researched as potential sources of novel drugs, which has led to a recent acceleration in the discovery of new bioactive compounds. Research on tissue culture technology for the synthesis and processing of plant compounds has skyrocketed, surpassing all expectations. These plants can be bought either raw or as extracts, where some of the chemicals are extracted by mashing the plant in water, alcohol, or another solvent. The use of herbal medicine may open new chances for reducing the onset of infections and treating different diseases including cancer. A perennial plant that blooms in the winter, Cyclamen, is one of the most widely used potted flowers in many nations. Alkaloids, flavonoids, phenols, tannins, saponins, sterols, and glycosides are the main active components of Cyclamen. Analgesic, cytotoxic, antioxidant, antimicrobial, and anti-inflammatory properties have all been demonstrated as potential effects of various extracts of Cyclamen tubers. However, the use of this medicinal plant in official medicine will require further research in the areas of pharmacology. Furthermore, it is necessary to create standard operating procedures for a crude herbal medication. In this regard, this review aims to highlight the key characteristics of the Cyclamen plant, such as its various parts, species, stages of development, and geographic range; pinpoint its intriguing bioactivities, its antioxidant, anti-inflammatory, and its anti-cancerous effects; and ascertain its potential medicinal uses and the main future perspectives.
... Even if the design or sampling of these studies were doubted, the findings were terrible. [13] ...
Although cancer remains a challenging disease to treat, early detection and removal of primary tumors through surgery or chemotherapy/radiotherapy can offer hope for patients. The privilege paradigm in cancer biology suggests that cell‐autonomous mechanisms play a central role in tumorigenesis. According to this paradigm, these cellular mechanisms are the primary focus for the prevention and treatment of cancers. However, this point of view does not present a comprehensive theory for the initiation of cancer and an effective therapeutic strategy. Having an incomplete understanding of the etiology of cancer, it is essential to re‐examine previous assumptions about carcinogenesis and develop new, practical theories that can account for all available clinical and experimental evidence. This will not only help to gain a better understanding of the disease, but also offer new avenues for treatment. This review provides evidence suggesting a shift in focus from a cell‐autonomous mechanism to systemic mechanisms, particularly the immune system, that are involved in cancer formation.
... With hormone therapy and a robust immune response, a breast tumor can be eradicated entirely or reduced to a minimal size where it poses no harm. According to several studies [38][39][40], a small tumor never develops into an aggressive type and is termed "cancer without disease." With hormone therapy and a typical immune response, a breast tumor can exist to a limited extent and may grow at the end of treatment. ...
Oncology research has focused extensively on estrogen hormones and their function in breast cancer proliferation. Mathematical modeling is essential for the analysis and simulation of breast cancers. This research presents a novel approach to examine the therapeutic and inhibitory effects of hormone and estrogen therapies on the onset of breast cancer. Our proposed mathematical model comprises a nonlinear coupled system of partial differential equations, capturing intricate interactions among estrogen, cytotoxic T lymphocytes, dormant cancer cells, and active cancer cells. The model's parameters are meticulously estimated through experimental studies, and we conduct a comprehensive global sensitivity analysis to assess the uncertainty of these parameter values. Remarkably, our findings underscore the pivotal role of hormone therapy in curtailing breast tumor growth by blocking estrogen's influence on cancer cells. Beyond this crucial insight, our proposed model offers an integrated framework to delve into the complexity of tumor progression and immune response under hormone therapy. We employ diverse experimental datasets encompassing gene expression profiles, spatial tumor morphology, and cellular interactions. Integrating multidimensional experimental data with mathematical models enhances our understanding of breast cancer dynamics and paves the way for personalized treatment strategies. Our study advances our comprehension of estrogen receptor-positive breast cancer and exemplifies a transformative approach that merges experimental data with cutting-edge mathematical modeling. This framework promises to illuminate the complexities of cancer progression and therapy, with broad implications for oncology.
... More importantly, enriched blood vessels would facilitate metastasis. [14,15] In this regard, inhibition of tumor angiogenesis becomes part of cancer therapeutic intervention, for example, the FDA-approved antiangiogenic drugs including sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), and everolimus (Afinitor), as well as those angiogenic antagonists under clinical trials. [16][17][18] In combination with chemotherapy or radiation, these drugs can significantly increase the survival rate. ...
In search of effective therapeutics for breast cancers, establishing physiologically relevant in vitro models is of great benefit to facilitate the clinical translation. Despite extensive progresses, it remains to develop the tumor models maximally recapturing the key pathophysiological attributes of their native counterparts. Therefore, the current study aimed to develop a microsphere‐enabled modular approach toward the formation of in vitro breast tumor models with the capability of incorporating various selected cells while retaining spatial organization. Poly (lactic‐co‐glycolic acid) microspheres (150‐200 mm) with tailorable pore size and surface topography are fabricated and used as carriers to respectively lade with breast tumor‐associated cells. Culture of cell‐laden microspheres assembled within a customized microfluidic chamber allowed to form 3D tumor models with spatially controlled cell distribution. The introduction of endothelial cell‐laden microspheres into cancer‐cell laden microspheres at different ratios would induce angiogenesis within the culture to yield vascularized tumor. Evaluation of anticancer drugs such as doxorubicin and Cediranib on the tumor models do demonstrate corresponding physiological responses. Clearly, with the ability to modulate microsphere morphology, cell composition and spatial distribution, microsphere‐enabled 3D tumor tissue formation offers a high flexibility to satisfy the needs for pathophysiological study, anticancer drug screening or design of personalized treatment.
... Consequently, cancer cells demonstrate a decline in response to this swift reaction by the CTLs and remain constant at a low quantity. This phenomenon, referred to as "cancer without disease", has been extensively studied, and several experimental studies indicate that small tumors do not grow to an invasive state [51][52][53]. ...
Breast cancer ranks among the most prevalent malignancies affecting the female population and is a prominent contributor to cancer-related mortality. Mathematical modeling is a significant tool that can be employed to comprehend the dynamics of breast cancer progression and dissemination and to formulate novel therapeutic approaches. This paper introduces a mathematical model of breast cancer that utilizes the Caputo–Fabrizio fractal-fractional derivative. The aim is to elucidate and comprehend the intricate dynamics governing breast cancer cells and cytotoxic T lymphocytes in the context of the fractional derivative. The derivative presented herein offers a broader perspective than the conventional derivative, as it incorporates the intricate fractal characteristics inherent in the process of tumor proliferation. The significance of this study lies in its contribution to a novel mathematical model for breast cancer, which incorporates the fractal characteristics of tumor development. The present model possesses the capability to investigate the impacts of diverse treatment strategies on the proliferation of breast cancer, as well as to formulate novel treatment strategies that exhibit enhanced efficacy.
... In contrast to rapidly growing cancers, a subset of cancers can exhibit very slow growth and may never become symptomatic or cause morbidity and mortality [1,2]. Some tumors are non-progressive cancers that remain dormant or may even regress, perhaps through the emergence of cellular senescence, immune predation, or outgrowth of vascular and metabolic support [1,[3][4][5]. ...
Certain medical diagnoses and environmental or occupational exposures may be associated with elevated risk of cancer diagnosis, either through causal mechanisms or via increased detection of a subclinical reservoir through increased diagnostic scrutiny (overdiagnosis). The present study aimed to investigate the distribution of elevated cancer risks associated with different diagnoses and exposures. A systematic literature search was conducted to identify studies published in the last 30 years that examined the standardized incidence ratio (SIR) associated with exposures and risk factors. Meta-SIRs for each cancer type were calculated. The distribution of elevated cancer risks was then compared between cancer types previously reported to be susceptible to overdiagnosis and those that have not been associated with overdiagnosis. The review of 108 studies identified four patterns: SIR generally elevated for 1) only overdiagnosis-susceptible cancer types, 2) both overdiagnosed and non-overdiagnosed cancer types, 3) select cancers in accordance with risk factor or exposure, and 4) SIRs that did not exhibit a distinct increase in any cancer type. The distribution of elevated cancer risks may serve as a signature of whether the underlying risk factor or exposure is a carcinogenic process or a mechanism of increased diagnostic scrutiny uncovering clinically occult diseases. The identification of increased cancer risk should be viewed with caution, and analyzing the pattern of elevated cancer risk distribution can potentially reveal conditions that appear to be cancer risk factors but are in fact the result of exposure to medical surveillance or other healthcare activities that lead to the detection of indolent tumors.
... However, the effect on the fitness may be small, as the cancer mortality risk of species did not scale with litter size and lactation length. It is likely that those oncogenic processes do not systematically impact the survival, or other fitness-related parameters in their hosts (see for instance [51]). Our results thus support the hypothesis that cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan with the mortality pattern of ageing individuals (see also [12,52]). ...
Reproduction is a central activity for all living organisms but is also associated with a diversity of costs that are detrimental for survival. Until recently, the cost of cancer as a selective force has been poorly considered. Considering 191 mammal species, we found cancer mortality was more likely to be detected in species having large, rather than low, litter sizes and long lactation lengths regardless of the placentation types. However, increasing litter size and gestation length are not per se associated with an enhanced cancer mortality risk. Contrary to basic theoretical expectations, the species with the highest cancer mortality were not those with the most invasive (i.e. haemochorial) placentation, but those with a moderately inva-sive (i.e. endotheliochorial) one. Overall, these results suggest that (i) high reproductive efforts favour oncogenic processes' dynamics, presumably because of trade-offs between allocation in reproduction effort and anti-cancer defences, (ii) cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan, and (iii) malignant cells co-opt existing molecular and physiological pathways for placentation, but species with the most invasive placentation have also selected for potent barriers against lethal cancers. This work suggests that the logic of Peto's paradox seems to be applicable to other traits that promote tumorigenesis.
... Moreover, the inclusion of non-progressive tumors or false positives (overdiagnosis bias) falsely inflates the survival rate (Folkman & Kalluri, 2004;Mooi & Peeper, 2006;Serrano, 2007). For many people, the expression "survival rate" incorrectly relates only to the probability of survival. ...
In order to make an informed, evidence-based decision, it is vital to recognize numbers, statistics and concepts that are apparently transparent but are not always adequately accounted for. Health professionals, patients, and others frequently misinterpret numbers, statistics and concepts in healthcare. Among the many repercussions of health literacy, appropriate decision-making and the reduction in the number of interventions and treatments stand out, resulting in an improvement in people's health and a decrease in overtreatment and health expenses. This study intends to evaluate how properly health professionals and the public, in general, comprehend and interpret some health-related numbers. To accomplish this goal, the researchers shared a questionnaire made available online in Portugal from January 2, 2019, until April 12, 2019. The final sample comprised 485 respondents; 154 physicians, 142 nurses, and 189 people from other professions. The findings suggest that there is a problem with widespread numerical illiteracy, which should not be the case, highlighting the need to improve the numerical and statistical health literacy of both health professionals and the general population. So, medical professionals and patients must thus comprehend the statistics and health-related concepts to obtain the proper consent.
... Figure 7D shows that OVT can reduce the tumor size and the tumor remains in an equilibrium state with a low population level. Equilibrium phase of immunoediting is a state in which the tumor remains small and stable due to the balance between immune response and tumor growth [67]. ...
We propose and study a mathematical model governing interactions between cancer and immune system with an oncolytic viral therapy (OVT), wherein cancer cells can activate and inhibit immune cells simultaneously with saturations. When the therapy is not applied, it is shown that the interaction can support at most three hyperbolic positive equilibria where two of them are always asymptotically stable and the other is a saddle point. The reachable stable tumor burden can be either small or large depending on initial tumor size. We analyze the full model by proving global asymptotic stability of the virus‐free equilibrium that corresponds to OVT failure. Sufficient conditions based on model parameters are derived under which the model is uniformly persistent. The proposed system is validated using a mouse model of human pancreatic cancer carried out by Koujima et al. Global sensitivity analysis indicates that the rates of tumor‐mediated killing and immune cell exhaustion are critical for tumor progression and therapy success. Numerical bifurcation analysis reveals that the saddle point can be utilized to estimate the maximum tumor load for eradication by OVT. Moreover, an immunosuppressive microenvironment may enhance viral therapy efficacy.
... Moreover, similar observations have been reported for men diagnosed with cancer. Although only 0.1% of men between the ages of 50-70 years are confirmed to have thyroid cancer, in situ carcinomas were detected in the thyroid glands of all autopsied men in this age group [100]. Although Richard Nixon declared war on cancer several decades ago, this disease is still a public health challenge presently, and research efforts on cures or management strategies for cancer are needed. ...
The discovery of nalidixic acid is one pinnacle in medicinal chemistry, which opened a new area of research that has led to the discovery of several life-saving antimicrobial agents (generally referred to as fluoroquinolones) for over decades. Although fluoroquinolones are frequently encountered in the literature, the utility of quinolone compounds extends far beyond the applications of fluoroquinolones. Quinolone-based compounds have been reported for activity against malaria, tuberculosis, fungal and helminth infections, etc. Hence, the quinolone scaffold is of great interest to several researchers in diverse disciplines. This article highlights the versatility of the quinolone pharmacophore as a therapeutic agent beyond the fluoroquinolone profile.
Graphical abstract
... One of the key mechanisms for the escape from tumor dormancy is the acquisition of the vascular phenotype (28,(32)(33)(34)(35). Multiple reports have demonstrated that dormant human tumors, namely lesions of fully transformed, proliferating neoplastic cells, remain in a dormant, harmless state in the absence of a vascular system (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). The escape from tumor dormancy has been shown to be required both at the earliest stage of a tumor's lifetime when it is ∼1 to 2 mm in diameter and not clinically detectable ("cancer without disease") (42), as well as during the activation of dormant metastatic lesions (43). We and others have previously identified and characterized a number of molecular determinants of the acquisition of the vascular phenotype (32,33,(39)(40)(41)44) as well as the role of the microenvironment in regulating tumor angiogenesis (45)(46)(47). ...
Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
... The genesis and development of malignant tumors depend on angiogenesis. Tumor angiogenesis is a complex process that is regulated by both angiogenic and angiosuppressive factors (Folkman and Kalluri, 2004). Neovascularization increases the blood supply to the tumor to better deliver oxygen and nutrients, allowing tumor cells to spread to distant sites (Verheul et al., 2004). ...
In observational studies, circulating vascular endothelial growth factor (VEGF) has been reported to be associated with certain types of cancer. The purpose of this study was to verify whether there is a causal relationship between circulating VEGF and different types of cancer and the direction of the causal relationship. Summary statistical data were obtained from the corresponding genome-wide association studies (GWASs) to investigate the causal relationship between circulating VEGF and the risk of several cancers, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, anus and anal canal cancer, prostate cancer, esophageal cancer, kidney cancer, bladder cancer, thyroid cancer, malignant neoplasm of the brain and malignant neoplasm of the liver and intrahepatic bile ducts. A two-sample bidirectional Mendelian randomization (MR) analysis and sensitivity tests were used to evaluate the validity of causality. A causal relationship was detected between circulating VEGF and colorectal cancer (OR 1.21, 95% CI 1.11–1.32, p < 0.000) and colon adenocarcinoma (OR 1.245, 95% CI 1.10–1.412, p < 0.000). Suggestive evidence of association was detected in VEGF on malignant neoplasms of the rectum (OR 1.16, 95% CI 1.00–1.34, p = 0.049). No causal relationship was found between circulating VEGF and other types of cancer, nor was there a reverse causal relationship from tumors to VEGF (p > 0.05). Circulating VEGF has a causal relationship with specific types of cancer. Our findings highlight and confirm the importance of circulating VEGF in the prevention and treatment of colorectal cancer.
... Epigenetics is the study of changes in heritable gene expression that lead to the proliferation of abnormal cells [2]. Cancer is caused by the abnormal function of the genes and the manipulated pattern of gene expression, loss of the process of normal cell growth, development, and control; malfunctioning of apoptosis; initiation of angiogenesis, and metastasizing to other healthy tissue or organs [3]. ...
Cancer is a serious and significantly progressive disease. Next to cardiovascular disease,
cancer has become the most common cause of mortality in the entire world. Several factors, such as environmental factors, habitual activities, genetic factors, etc., are responsible for cancer. Many cancer patients seek alternative and/or complementary treatments because of the high death rate linked with cancer and the adverse side effects of chemotherapy and radiation therapy. Traditional medicine has a long history that begins with the hunt for botanicals to heal various diseases, including cancer.
In the traditional medicinal system, several plants used to treat diseases have many bioactive compounds with curative capability, thereby also helping in disease prevention. Plants also significantly contributed to the modern pharmaceutical industry throughout the world. In the present review, we have listed 33 medicinal plants with active and significant anticancer activity, as well as their anticancer compounds. This article will provide a basic set of information for researchers interested in developing a safe and nontoxic active medicinal plant-based treatment for cancer. The research will give a scientific foundation for the traditional usage of these medicinal herbs to treat cancer.
... While this review focuses on the abundant clonal expansions in our tissues that are largely driven by single mutations, we must also consider the mechanisms that help to eliminate early tumors, like carcinomas. Carcinomas in situ are very common in tissues like the prostate, breast, and thyroid in old adults, far outpacing the frequency of the associated cancers [146]. It is therefore important to determine what keeps these carcinomas in check. ...
Aging represents the major risk factor for the development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones that are frequently driven by cancer‐associated mutations in an aging‐dependent fashion. Additional studies show how aged tissue microenvironments promote the initiation and progression of malignancies, while young healthy tissues actively suppress the outgrowth of malignant clones. Here, we discuss conserved mechanisms that eliminate poorly functioning or potentially malignant cells from our tissues to maintain organismal health and fitness. Natural selection acts to preserve tissue function and prevent disease to maximize reproductive success but these mechanisms wane as reproduction becomes less likely. The ensuing age‐dependent tissue decline can impact the shape and direction of clonal somatic evolution, with lifestyle and exposures influencing its pace and intensity. We also consider how aging‐ and exposure‐dependent clonal expansions of “oncogenic” mutations might both increase cancer risk late in life and contribute to tissue decline and non‐malignant disease. Still, we can marvel at the ability of our bodies to avoid cancers and other diseases despite the accumulation of billions of cells with cancer‐associated mutations.
... While the importance of early detection is recognised, prevention of identified risk factors can promote the prevention of certain cancers, it should not be forgotten that others have a bleak prognosis from the time of diagnosis. While classical treatment resources and their combinations have contributed to improve the quality of life and survival of patients, mortality rates remain unchanged and are expected to worsen in the coming years, therefore new therapeutic tools are needed [34]. There is currently a wide range of research underway on cancer treatment, including advances in molecular biology that have promoted the use of viruses as specific vectors for cancer treatment, a fact that has been known since the beginning of the last century. ...
Celyvir viro-immunotherapy - a therapy using mesenchymal stem cells (MSCs) infected with the oncolytic adenovirus ICOVIR 5, an innovative oncolytic adenovirus - is a new therapeutic approach in cancer treatment. The purpose of this study is to create a mathematical model describing the relationships between immune, cancer and viral cells in pediatric patients with neuroblastoma. This was done by studying two different ways of applying the treatment: continuous and periodic therapy. Analysis of the first mathematical model identifies equilibrium points, their stability properties and bifurcation points. It can also identify bistability regimes in which therapy can induce either tumour-free equilibrium or tumour progression, depending only on the initial conditions. The second model reveals the existence of a threshold value of viral load, beyond which the patient’s recovery could be assured. The models make it clear that both the intensity of the viral load and the time over which treatment is given must be sufficient to ensure the success of the therapy. Low levels of treatment may fail to eliminate neuroblastoma, while stopping therapy early could lead to recurrence.
... Cancer occurs when individual cells become malignant, i.e., lose their normal cooperative behavior, become insensitive to host controls, proliferate in an uncontrolled fashion, and spread from primary tumors to surrounding tissues and then to distant organs (i.e., metastasis), thereby causing morbidity and potentially death (Hanahan and Weinberg, 2011). Chronological age is indisputably the most significant risk factor (in terms of incidence) for developing metastatic cancer, but it is also well established that oncogenic processes frequently exist at sub-clinical levels earlier in life (in humans and other animals, Folkman and Kalluri, 2004;Bissell and Hines, 2011;Madsen et al., 2017), and in fact represent a long continuum between precancerous lesions to invasive forms (Maley et al., 2017). Recent advances in oncology suggest that pathogens, parasites, viruses, or transposable elements may be the most common causes of cancer in wildlife, while second-hand smoke, nutritional challenges, breeding stress, UV radiation, and chemicals in the environment causing somatic mutations may be most important for pets and humans (Aktipis and Nesse, 2013;Giraudeau et al., 2018;Pesavento et al., 2018). ...
Reproduction is one of the most energetically demanding life-history stages. As a result, breeding individuals often experience trade-offs, where energy is diverted away from maintenance (cell repair, immune function) toward reproduction. While it is increasingly acknowledged that oncogenic processes are omnipresent, evolving and opportunistic entities in the bodies of metazoans, the associations among reproductive activities, energy expenditure, and the dynamics of malignant cells have rarely been studied. Here, we review the diverse ways in which age-specific reproductive performance (e.g., reproductive aging patterns) and cancer risks throughout the life course may be linked via trade-offs or other mechanisms, as well as discuss situations where trade-offs may not exist. We argue that the interactions between host–oncogenic processes should play a significant role in life-history theory, and suggest some avenues for future research.
... In literature, it is reported that if a tumour has a diameter of less than 2 mm and the population level remains under 6 × 10 5 , then the tumour remains small and stable [58] . This phenomenon is known as cancer without disease, and several studies have suggested that microscopic tumours never grow to invasive tumours [59][60][61] . The numerical simulation results support the results of the stability and sensitivity analyses. ...
Over the past few decades, there have been significant advances in clinical, experimental, and theoretical frameworks for understanding cancer cells’ complexities and their interactions with the immune system. Breast cancer progression is associated with estrogen signalling and the estrogen receptor (ER), and the majority of human breast cancers originate as estrogen-dependent. Additionally, mounting data indicate that ER signalling is complicated, comprising both coregulatory proteins and extranuclear actions. This paper deals with a mathematical model of the tumour-immune response incorporating anti-tumour cytokines and estrogen. The designed model is formulated based on a detailed phenomenological description of the kinetic theory of tumour, immune system and estrogen. The experimental studies are used to estimate the model’s parameters, and the Lyapunov approach is used to determine the stability of equilibrium points. Monte-Carlo-Markov-Chain (MCMC) methods have been used extensively to deal with the nonlinear fractals, and in the field of artificial intelligence for the evaluation of the parameters. In this manuscript, the sensitivity analysis is conducted to assess the parameters’ uncertainty with the aid of AI-MCMC toolbox. The numerical simulations of the model support the results of clinical studies. Furthermore, we discuss the pharmacokinetics and pharmacodynamics of chemotherapy and introduce cellular immunotherapy as treatments for boosting immune cells to fight against tumours. Our findings seem to indicate that the proposed model is a strong candidate for studying the dynamics of estrogen, and it helps in the provision of complex interactions of estrogen with breast tumours and immune cells.
... There are multiple accompanying mechanisms which may contribute to thyroid cancer recurrence, including increased angiogenesis (16), escape from immune detection (17) and changes in the extracellular matrix (15). Investigating alterations in such pathways to identify significant biomarkers of thyroid cancer recurrence is important due to the significant morbidity and mortality associated with recurrence. ...
Background
Thyroid cancer recurrence is associated with increased mortality and adverse outcomes. Recurrence risk is currently predicted using clinical tools, often restaging patients after treatment. Detailed understanding of recurrence risk at disease-onset could lead to personalised and improved patient care.
Objective
To perform a comprehensive bioinformatic and experimental analysis of 3 levels of genetic change (mRNA, microRNA, and somatic mutation) apparent in recurrent tumours and construct a new combinatorial prognostic risk model.
Methods
We analysed The Cancer Genome Atlas data (TCGA) to identify differentially expressed genes (mRNA/microRNA) in 46 recurrent versus 455 non-recurrent thyroid tumours. Two exonic mutational pipelines were used to identify somatic mutations. Functional gene analysis was performed in cell-based assays in multiple thyroid cell lines. The prognostic value of genes was evaluated with TCGA datasets.
Results
We identified a total of 128 new potential biomarkers associated with recurrence, including 40 mRNAs, 39 miRNAs and 59 genetic variants. Among differentially expressed genes, modulation of FN1, ITGα3 and MET had a significant impact on thyroid cancer cell migration. Similarly, ablation of miR-486 and miR-1179 significantly increased migration of TPC-1 and SW1736 cells. We further utilised genes with a validated functional role and identified a 5 gene risk score classifier as an independent predictor of thyroid cancer recurrence.
Conclusions
Our newly proposed risk model based on combinatorial mRNA and microRNA expression has potential clinical utility as a prognostic indicator of recurrence. These findings should facilitate earlier prediction of recurrence with implications for improving patient outcome by tailoring treatment to disease risk and increasing post-treatment surveillance.
... Evolving concepts of dormancy are providing clarity to two major challenges in oncology: asymptomatic minimal residual disease (MRD) [15] and cancers of unknown primary (CUP) [16,17]. MRD is asymptomatic and often undetectable; however, small clusters of residual tumor cells remain within secondary sites throughout the body and-upon specific stimuli, including increasing chronic inflammation and immune suppression-can emerge as recurrent, metastatic disease. ...
Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers.
... Multicellular organisms are generally composed of normal cooperating cells, but can also harbor host cells that proliferate abnormally and form masses called tumors or neoplasms [1]. Tumors are usually classified into two main categories: benign or malignant. ...
Tumors are usually classified into two main categories – benign or malignant, with much more attention being devoted to the second category given that they are usually associated with more severe health issues (i.e., metastatic cancers). Here, we argue that the mechanistic distinction between benign and malignant tumors has narrowed our understanding of neoplastic processes. This review provides the first comprehensive discussion of benign tumors in the context of their evolution and ecology as well as interactions with their hosts. We compare the genetic and epigenetic profiles, cellular activities, and the involvement of viruses in benign and malignant tumors. We also address the impact of intra-tumoral cell composition and its relationship with the tumoral microenvironment. Lastly, we explore the differences in the distribution of benign and malignant neoplasia across the tree of life and provide examples on how benign tumors can also affect individual fitness and consequently the evolutionary trajectories of populations and species. Overall, our goal is to bring attention to the non-cancerous manifestations of tumors, at different scales, and to stimulate research on the evolutionary ecology of host–tumor interactions on a broader scale. Ultimately, we suggest that a better appreciation of the differences and similarities between benign and malignant tumors is fundamental to our understanding of malignancy both at mechanistic and evolutionary levels.
... 27 Now a days, cancer is one of the prominent, non-curable and lifethreatening disease. 200,319,430 Till date, there is no definite, curable and life-saving strategy in cancer therapy. 431,432 Furthermore, as reported till date, CHIP has its antitumorigenic effects by ubiquitination and degradation of several target onco-proteins in different cancers. ...
The carboxy-terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase and co-chaperone belonging to Ubox family that plays a crucial role in the maintenance of cellular homeostasis by switching the equilibrium of the folding-refolding mechanism towards the proteasomal or lysosomal degradation pathway. It links molecular chaperones viz. HSC70, HSP70 and HSP90 with ubiquitin proteasome system (UPS), acts as a quality control system. CHIP contains charged domain in between N-terminal TPR and C-terminal Ubox domain. TPR domain interacts with the aberrant client proteins via chaperones while Ubox domain facilitates the ubiquitin transfer to the client proteins for ubiquitination. Thus, CHIP is a classic molecule that executes ubiquitination for degradation of client proteins. Further, CHIP has been found to be indulged in cellular differentiation, proliferation, metastasis and tumorigenesis. Additionally, CHIP can play its dual role as a tumor suppressor as well as an oncogene in numerous malignancies, thus acts as a double agent. Here, in this review, we have reported almost all substrates of CHIP established till date and classified them according to the hallmarks of cancer. In addition, we discussed about its architectural alignment, tissue specific expression, sub-cellular localization, folding-refolding mechanisms of client proteins, E4 ligase activity, normal physiological roles, involvement in various diseases and tumor biology. Further, we aim to discuss its importance in HSP90 inhibitors mediated cancer therapy. Thus, this report concludes that CHIP may be a promising and worthy drug target towards pharmaceutical industry for drug development.
In this chapter, we will take an in-depth look at the role of physical activity in cancer prevention and treatment. We will explore how an active lifestyle can reduce the risk of certain types of cancer and how exercise can influence cancer cells’ development, proliferation and survival. In addition, we will discuss the different types of exercise, such as aerobic exercise and resistance training, and their specific effects on cancer cells. We will also emphasize the supportive role of exercise in reducing side effects of cancer treatment, improving physical performance, and promoting a positive outlook on life in cancer patients. Furthermore, we will discuss the recommendations for physical activity in cancer survivors and the importance of moderate exercise for health and well-being. Finally, we will summarize the benefits of regular exercise for cancer prevention and treatment and present strategies to increase physical activity in everyday life.
After talking about the normal cell, its division and the cell cycle, we move on to tackling the concept of cancer. Despite being a daunting word, it is worth understanding what cancer patients deal with. We will also cover examinations and treatments at a later stage. Our goal is to help lessen the “loss of control” and helplessness that cancer patients often feel.
Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.
Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. Here, we elucidate how bone metastasis arises from tumor cells that detach from the primary lesions and infiltrate into the surrounding tissue, as well as how these cells disseminate to distant sites. Specifically, we elaborate how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.
Cell migration is a fundamental process intimately underlying the development of multicellular organisms, and its dysregulation is associated with a variety of diseases. The ability to confidently navigate a complex extracellular space is at the core of an effective immune response. Indeed, motility represents a key aspect of immune cell behavior, fundamental to eliminating invading pathogens, scanning tissues for damage, and detecting developing tumors. The convenience of live imaging and the genetic tractability of certain in vivo model organisms (i.e., flies and zebrafish) offer a unique opportunity to better understand mechanisms of immune cell motility in an in vivo context and to gain novel insights into how these cells fulfill their numerous functions by promptly modifying their migratory behavior in response to a wide variety of extrinsic cues.
Our knowledge of fluorine's unique and complex properties has significantly increased over the past 20 years. Consequently, more sophisticated and innovative techniques have emerged to incorporate this feature into the design of potential drug candidates. In recent years, researchers have become interested in synthesizing fluoro-sulphonamide compounds to discover new chemical entities with distinct and unexpected physical, chemical, and biological characteristics. The fluorinated sulphonamide molecules have shown significant biomedical importance. Their potential is not limited to biomedical applications but also includes crop protection. The discovery of novel fluorine and Sulfur compounds has highlighted their importance in the chemical sector, particularly in the agrochemical and medicinal fields. Recently, several fluorinated sulphonamide derivatives have been developed and frequently used by agriculturalists to produce food for the growing global population. These molecules have also exhibited their potential in health by inhibiting various human diseases. In today's world, it is crucial to have a steady supply of innovative pharmaceutical and agrochemical molecules that are highly effective, less harmful to the environment, and affordable. This review summarizes the available information on the activity of Fluorine and Sulphonamide compounds, which have proven active in pharmaceuticals and agrochemicals with excellent environmental and human health approaches. Moreover, it focuses on the current literature on the chemical structures, the application of fluorinated sulphonamide compounds against various pathological conditions, and their effectiveness in crop protection.
Angiogenesis is the process of formation of new blood vessels in tissues and organs, which occurs with the participation of many factors. Angiogenesis can be influenced by various factors, such as mechanical tissue stretching, hypoxia, infections, inflammation, and others. Understanding these mechanisms can be important for the development of new approaches to the treatment of various diseases associated with angiogenesis disorders. The process of angiogenesis plays an important role in various physiological and pathological conditions, such as wound healing, tissue regeneration, tumor development, and others. Regulation of angiogenesis can be used for the treatment of diseases associated with a lack of blood circulation. Knowledge about angiogenesis can also be useful for planning and conducting surgery, to increase the efficiency of the surgery, which can help significantly reduce the risk of complications, and avoid repeated interventions. Purpose - to search and analyze the recent publications to identify trends in the direction of influence on vascular growth. The search for publications was carried out in well-known global scientometric databases, the range of which spanned more than 10 years. Published results of many years of research, factors and methods of influence on angiogenesis were found and analyzed. To date, the questions of the impact on angiogenesis remain open, which calls for further research and study of new methods and improvement of existing ones, since knowledge about the mechanisms of angiogenesis can help to develop new methods of treatment and prevention of various diseases. No conflict of interests was declared by the authors.
This review paper has highlighted a list of plants containing active phytochemicals with anticancer potential, as well as data supporting their use in cancer therapy, animal models, and their pharmacological properties. Cancer is among the leading causes of morbidity and mortality worldwide. Cancer is a disease characterized by abnormal cell division and proliferation that result from disruption of molecular signals that control these processes. Cancer is the abnormal, uncontrolled division of cells in the body. The cancer cells when malignant, invade various parts of the body through the bloodstream. The spread of cancer from its cells or tissue of origin to another healthy part of tissues or organs is called metastasis. Some of the regular characteristics of cancers are apoptosis, angiogenesis, multiple replication, growth signal production, insensitivity to signals of anti-growth and metastasis. These features make cancer cells to have continuous growth, long time survival and the potential to invade normal cells. Moreover, if these activities are not blocked, cancer cells will continue to increase, overwhelm and finally kill the patient with cancer. Oncology is the study of cancer. An oncologist is a doctor who treats cancer and provides medical care for a person diagnosed with cancer. An oncologist may also be called a cancer specialist. Today, despite considerable efforts, cancer still remains an aggressive killer worldwide. The success rate of these therapies is diminished by toxicities, drug resistance, recurrence and treatment failure. A significant challenge associated with cancer is that treatment is as much an art as it is a science. Therefore, there is a constant demand to develop new, effective, and affordable anticancer drugs. Several factors, such as environmental factors, habitual activities, genetic factors, etc., are responsible for cancer. Many cancer patients seek alternative and/or complementary treatments because of the high death rate linked with cancer and the adverse side effects of chemotherapy, radiation therapy, immunotherapy, surgery, and stem cell therapy. Medicinal plants could also possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity; such as chemotherapy-induced nausea and vomiting to improve patients' quality of life. Cell death is caused by the whole plant extracts via apoptosis. However, majority of plant extracts have been researched for cancer prevention rather than treatment, resulting in low efficacy and uptake in practice. Prevention is certainly an attractive cancer management strategy. Thus it might be possible to reduce the process of carcinogenesis with regular use of these plants along with a healthy lifestyle.
This review paper has highlighted a list of plants containing active phytochemicals with anticancer potential, as well as data supporting their use in cancer therapy, animal models, and their pharmacological properties. Cancer is among the leading causes of morbidity and mortality worldwide. Cancer is a disease characterized by abnormal cell division and proliferation that result from disruption of molecular signals that control these processes. Cancer is the abnormal, uncontrolled division of cells in the body. The cancer cells when malignant, invade various parts of the body through the bloodstream. The spread of cancer from its cells or tissue of origin to another healthy part of tissues or organs is called metastasis. Some of the regular characteristics of cancers are apoptosis, angiogenesis, multiple replication, growth signal production, insensitivity to signals of anti-growth and metastasis. These features make cancer cells to have continuous growth, long time survival and the potential to invade normal cells. Moreover, if these activities are not blocked, cancer cells will continue to increase, overwhelm and finally kill the patient with cancer. Oncology is the study of cancer. An oncologist is a doctor who treats cancer and provides medical care for a person diagnosed with cancer. An oncologist may also be called a cancer specialist. Today, despite considerable efforts, cancer still remains an aggressive killer worldwide. The success rate of these therapies is diminished by toxicities, drug resistance, recurrence and treatment failure. A significant challenge associated with cancer is that treatment is as much an art as it is a science. Therefore, there is a constant demand to develop new, effective, and affordable anticancer drugs. Several factors, such as environmental factors, habitual activities, genetic factors, etc., are responsible for cancer. Many cancer patients seek alternative and/or complementary treatments because of the high death rate linked with cancer and the adverse side effects of chemotherapy, radiation therapy, immunotherapy, surgery, and stem cell therapy. Medicinal plants could also possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity; such as chemotherapy-induced nausea and vomiting to improve patients' quality of life. Cell death is caused by the whole plant extracts via apoptosis. However, majority of plant extracts have been researched for cancer prevention rather than treatment, resulting in low efficacy and uptake in practice. Prevention is certainly an attractive cancer management strategy. Thus it might be possible to reduce the process of carcinogenesis with regular use of these plants along with a healthy lifestyle.
Cancer is among the leading causes of morbidity and mortality worldwide. Cancer is a disease characterized by abnormal cell division and proliferation that result from disruption of molecular signals that control these processes. Cancer is the abnormal, uncontrolled division of cells in the body. The cancer cells when malignant, invade various parts of the body through the bloodstream. The spread of cancer from its cells or tissue of origin to another healthy part of tissues or organs is called metastasis. Some of the regular characteristics of cancers are apoptosis, angiogenesis, multiple replication, growth signal production, insensitivity to signals of anti-growth and metastasis. These features make cancer cells to have continuous growth, long time survival and the potential to invade normal cells. Moreover, if these activities are not blocked, cancer cells will continue to increase, overwhelm and finally kill the patient with cancer. Oncology is the study of cancer. An oncologist is a doctor who treats cancer and provides medical care for a person diagnosed with cancer. An oncologist may also be called a cancer specialist. Today, despite considerable efforts, cancer still remains an aggressive killer worldwide. The success rate of these therapies is diminished by toxicities, drug resistance, recurrence and treatment failure. A significant challenge associated with cancer is that treatment is as much an art as it is a science. Therefore, there is a constant demand to develop new, effective, and affordable anticancer drugs. Several factors, such as environmental factors, habitual activities, genetic factors, etc., are responsible for cancer. Many cancer patients seek alternative and/or complementary treatments because of the high death rate linked with cancer and the adverse side effects of chemotherapy, radiation therapy, immunotherapy, surgery, and stem cell therapy. Medicinal plants could also possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity; such as chemotherapy-induced nausea and vomiting to improve patients’ quality of life. Cell death is caused by the whole plant extracts via apoptosis. However, majority of plant extracts have been researched for cancer prevention rather than treatment, resulting in low efficacy and uptake in practice. Prevention is certainly an attractive cancer management strategy. Thus it might be possible to reduce the process of carcinogenesis with regular use of these plants along with a healthy lifestyle.
Peto’s paradox and the epidemiologic observation of the average six degrees of tumor prevalence are studied and hypothetically solved. A simple consideration, Petho’s paradox challenges our intuitive understanding of cancer risk and prevalence. Our simple consideration is that the more a cell divides, the higher the chance of acquiring cancerous mutations, and so the larger or longer-lived organisms have more cells and undergo more cell divisions over their lifetime, expecting to have a higher risk of developing cancer. Paradoxically, it is not supported by the observations. The allometric scaling of species could answer the Peto paradox. Another paradoxical human epidemiology observation in six average mutations is necessary for cancer prevalence, despite the random expectations of the tumor causes. To solve this challenge, game theory could be applied. The inherited and random DNA mutations in the replication process nonlinearly drive cancer development. The statistical variance concept does not reasonably describe tumor development. Instead, the Darwinian natural selection principle is applied. The mutations in the healthy organism’s cellular population can serve the species’ evolutionary adaptation by the selective pressure of the circumstances. Still, some cells collect multiple uncorrected mutations, adapt to the extreme stress in the stromal environment, and develop subclinical phases of cancer in the individual. This process needs extensive subsequent DNA replications to heritage and collect additional mutations, which are only marginal alone. Still, together, they are preparing for the first stage of the precancerous condition. In the second stage, when one of the caretaker genes is accidentally mutated, the caused genetic instability prepares the cell to fight for its survival and avoid apoptosis. This can be described as a competitive game. In the third stage, the precancerous cell develops uncontrolled proliferation with the damaged gatekeeper gene and forces the new game strategy with binary cooperation with stromal cells for alimentation. In the fourth stage, the starving conditions cause a game change again, starting a cooperative game, where the malignant cells cooperate and force the cooperation of the stromal host, too. In the fifth stage, the resetting of homeostasis finishes the subclinical stage, and in the fifth stage, the clinical phase starts. The prevention of the development of mutated cells is more complex than averting exposure to mutagens from the environment throughout the organism’s lifetime. Mutagenic exposure can increase the otherwise random imperfect DNA reproduction, increasing the likelihood of cancer development, but mutations exist. Toxic exposure is more challenging; it may select the tolerant cells on this particular toxic stress, so these mutations have more facility to avoid apoptosis in otherwise collected random mutational states.
From basic principles to insights into pioneering research, this introductory textbook provides the fundamentals of cancer biology that will enable students of biology and medicine to enter the field with confidence. It opens with a discussion of global cancer patterns, how cancers arise, and the risk factors involved. A description of the normal signalling pathways within cells then explains how DNA mutations affect proteins and what this means for the development and behaviour of tumours. Later chapters discuss methods for tumour detection, biomarker identification and the impact of genome sequencing, before reviewing the development of anti-cancer drugs and exciting current advances in treatment. With 50% new material, including two new chapters on genetic analysis of cancer and cancer chemotherapy, improved pedagogy, examples of revolutionising technologies in drug design and delivery, and useful online resources, this textbook offers an accessible and engaging account of cancer biology for undergraduate and graduate students.
Overview
Angiogenesis, the growth of new capillary blood vessels, is central to cancer growth and metastasis and is recognized to be a potential therapeutic target for the treatment of cancer. Antiangiogenic agents have become part of the standard treatment armamentarium for many solid tumors, providing significant clinical benefits for some cancers (e.g., renal cell, colorectal) and modest or no benefit for others. This article is focused on principles of tumor angiogenesis that are intrinsic to the behavior of human cancer, and lessons that can be gleaned from the clinical testing and use of angiogenesis inhibitors alone and in combination with other agents to date.
Considerable progress has been made in our understanding of the process of angiogenesis in the context of normal and tumor tissue over the last fifty years. Angiogenesis, like most physiological processes, is carefully controlled by dynamic and opposing effects of positive factors, such as vascular endothelial growth factor (VEGF), and negative factors, such as thrombospondin-1. In most cases, the progression of a small mass of cancerous cells to a life-threatening tumor depends upon the initiation of angiogenesis and involves the dysregulation of the angiogenic balance. Whereas our newfound appreciation for the role of angiogenesis in cancer has opened up new avenues for treatment, the success of these treatments, which have focused almost exclusively on antagonizing the VEGF pathway, has been limited to date. It is anticipated that this situation will improve as more therapeutics that target other pathways are developed, more strategies for combination therapies are advanced, more detailed stratification of patient populations occurs, and a better understanding of resistance to anti-angiogenic therapy is gained.
Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet‐hedging are identical or rather display distinct features. Here we argue that bet‐hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet‐hedging strategies in cancer originate from a hijacking of the normal developmental bet‐hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet‐hedging strategies of cancer cells. From stem/progenitor cells with highly stochastic gene expression, either a developmental bet‐hedging leading to stochasticity‐based tissue structuration occurs if the microenvironment is normal, or an atavistic bet‐hedging leading to cells with a continuum of differentiated states with high cellular plasticity occurs if the microenvironment is disrupted.
Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their “awakening” is still controversial. This review will focus on cancer cells’ microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response.
Although great effort has been expended to understand cancer's origins, less attention has been given to the primary cause of cancer deaths - cancer recurrences and their sequelae. This interdisciplinary review addresses mechanistic features of aggressive cancer by studying metabolic enzyme patterns within ductal carcinoma in situ (DCIS) of the breast lesions. DCIS lesions from patients who did or did not experience a breast cancer recurrence were compared. Several proteins, including phospho-Ser226-glucose transporter type 1, phosphofructokinase type L and phosphofructokinase/fructose 2,6-bisphosphatase type 4 are found in nucleoli of ductal epithelial cells in samples from patients who will not subsequently recur, but traffic to the cell periphery in samples from patients who will experience a cancer recurrence. Large co-clusters of enzymes near plasmalemmata will enhance product formation because enzyme concentrations in clusters are very high while solvent molecules and solutes diffuse through small channels. These structural changes will accelerate aerobic glycolysis. Agglomerations of pentose phosphate pathway and glutathione synthesis enzymes enhance GSH formation. As aggressive cancer lesions are incomplete at early stages, they may be unrecognizable. We have found that machine learning provides superior analyses of tissue images and may be used to identify biomarker patterns associated with recurrent and non-recurrent patients with high accuracy. This suggests a new prognostic test to predict DCIS patients who are likely to recur and those who are at low risk for recurrence. Mechanistic interpretations provide a deeper understanding of anti-cancer drug action and suggest that aggressive metastatic cancer cells are sensitive to reductive chemotherapy.
Non-proteincoding transcripts bearing 200 base pairs known as long non-coding RNAs (lncRNAs) play a role in a variety of molecular mechanisms, including cell differentiation, apoptosis and metastasis. Previous studies have suggested that frequently dysregulated lncRNAs play a crucial role in various aspects of cancer metastasis. Metastasis is the main leading cause of death in cancer. The role of lncRNAs in different stages of metastasis is the subject of this review. Based on in vitro and in vivo investigations on metastasis, we categorized lncRNAs into distinct stages of metastasis including angiogenesis, invasion, intravasation, survival in circulation, and extravasation. The involvement of lncRNAs in angiogenesis and invasion has been extensively studied. Here, we comprehensively discuss the role and functions of these lncRNAs with a particular focus on the molecular mechanisms.
We demonstrate a physiological role for tumstatin, a cleavage fragment of the α3 chain of type IV collagen (Col IVα3), which is present in the circulation. Mice with a genetic deletion of Col IVα3 show accelerated tumor growth associated with enhanced pathological angiogenesis, while angiogenesis associated with development and tissue repair are unaffected. Supplementing Col IVα3-deficient mice with recombinant tumstatin to a normal physiological concentration abolishes the increased rate of tumor growth. The suppressive effects of tumstatin require αVβ3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels. Mice deficient in matrix metalloproteinase-9, which cleaves tumstatin efficiently from Col IVα3, have decreased circulating tumstatin and accelerated growth of tumor. These results indicate that MMP-generated fragments of basement membrane collagen can have endogenous function as integrin-mediated suppressors of pathologic angiogenesis and tumor growth.
We wish to thank Jeff Arbeit, Karen Smith-McCune, Noel Weidner, Ella Bossy-Wetzel, and Christine Jolicoeur for providing the tissue sections used to prepare Figure 3Figure 3; Noel Bouck, Karen Smith-McCune, David Olson, Dowdy Jackson, and Jeff Arbeit for comments on the manuscript; and Wendy Gee and Terry Schoop of BioMed Arts (San Francisco) for artwork. The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.
Some human tumor lines do not form visible tumors when inoculated into immunosuppressed mice. The fate of these human tumor lines was followed by transfecting them with green fluorescence protein before inoculating them into mice. Although the tumor lines failed to grow progressively, they formed small dormant microscopic foci maintained at constant mass by balanced proliferation and apoptosis. Transfecting the cells with either VEGF165 or activated c-Ha-ras induced loss of dormancy, which correlated with a shift in the angiogenic balance toward increased vascularity with reduced tumor cell apoptosis. These results support a model in which loss of dormancy is controlled in part by a switch to an angiogenic phenotype. These tumor lines may serve as models for investigating the cellular mechanisms controlling dormancy and identifying those factors that promote the loss of balanced proliferation and apoptosis. Finally, these models may prove useful in the design and testing of therapies directed toward eradicating dormant tumors and preventing tumor recurrence.
In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.