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The competition of ecological resonances in the quantum metabolic model of cancer: Potential energetic interventions
Abstract
Cancer (a) represents an atavistic reversion to attempted asexual reproduction; (b) metastasizes to absorber “soil” tissues based upon temporal, ontogenetic commonalities; (c) cycles/precesses with competitive immunological surveillance and self-competition within the ecological environment of the body; and (d) is potentially manageable via quantum information qubit phase transitions and universal principles of thermodynamic hysteresis and resonant driving forces . We use retro-recognition of evidence-based cancer anomalies to make these arguments, which in sum position cancer as an ecological quantum information problem. The findings reposition the quantum metabolic model of cancer and presents a research approach aimed at applied treatments: Tertiary Lymphoid Structure ecological competition with cellular transmembrane quantum energy boosting using VDAC and other voltage gated ion channels.
Cancer therapy is facing increasingly significant challenges, marked by a wide range of techniques and research efforts centered around somatic mutations, precision oncology, and the vast amount of big data. Despite this abundance of information, the quest to cure cancer often seems more elusive, with the “war on cancer” yet to deliver a definitive victory. A particularly pressing issue is the development of tumor treatment resistance, highlighting the urgent need for innovative approaches. Evolutionary, Quantum Biology and System Biology offer a promising framework for advancing experimental cancer research. By integrating theoretical studies, translational methods, and flexible multidisciplinary clinical research, there’s potential to enhance current treatment strategies and improve outcomes for cancer patients. Establishing stronger links between evolutionary, quantum, entropy and chaos principles and oncology could lead to more effective treatments that leverage an understanding of the tumor’s evolutionary dynamics, paving the way for novel methods to control and mitigate cancer. Achieving these objectives necessitates a commitment to multidisciplinary and interprofessional collaboration at the heart of both research and clinical endeavors in oncology. This entails dismantling silos between disciplines, encouraging open communication and data sharing, and integrating diverse viewpoints and expertise from the outset of research projects. Being receptive to new scientific discoveries and responsive to how patients react to treatments is also crucial. Such strategies are key to keeping the field of oncology at the forefront of effective cancer management, ensuring patients receive the most personalized and effective care. Ultimately, this approach aims to push the boundaries of cancer understanding, treating it as a manageable chronic condition, aiming to extend life expectancy and enhance patient quality of life.
Lymphoma represents a myriad collection of neoplasms that impact lymphocytes. This cancer often involves disrupted cytokine, immune surveillance, and gene regulatory signaling, sometimes with expression of Epstein Barr Virus (EBV). We explored mutation patterns for People experiencing Lymphoma (PeL) in the National Cancer Institute (NCI) Genomic Data Commons (GDC), which contains detailed, deidentified genomic data on 86,046 people who have/had cancer with 2,730,388 distinctive mutations in 21,773 genes. The database included information on 536 (PeL), with the primary focal sample being the n = 30 who had complete mutational genomic data. We used correlations, independent samples t-tests, and linear regression to compare PeL demographics and vital status on mutation numbers, BMI, and mutation deleterious score across functional categories of 23 genes. PeL demonstrated varied patterns of mutated genes, consistent with most other cancer types. The primary PeL gene mutations clustered around five functional protein groups: transcriptional regulatory proteins, TNF/NFKB and cell signaling regulators, cytokine signaling proteins, cell cycle regulators, and immunoglobulins. Diagnosis Age, Birth Year, and BMI negatively (P < 0.05) correlated with Days to Death, and cell cycle mutations negatively correlated (P = 0.004) with survival days (R2 = 0.389). There were commonalities in some PeL for mutations across other cancer types based upon large sequence length, but also for 6 small cell lung cancer genes. Immunoglobulin mutations were prevalent but not for all cases. Research indicates a need for greater personalized genomics and multi-level systems analysis to evaluate facilitators and barriers for lymphoma survival.
Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.
Tumor-initiating cells (TICs) are a rare sub-population of cells within the bulk of a tumor that are major contributors to tumor initiation, metastasis, and chemoresistance. TICs have a stem-cell-like phenotype that is dictated by the expression of master regulator transcription factors, including OCT4, NANOG, and SOX2. These transcription factors are expressed via activation of multiple signaling pathways that drive cancer initiation and progression. Importantly, these same signaling pathways can be activated by select chemokine receptors. Chemokine receptors are increasingly being revealed as major drivers of the TIC phenotype, as their signaling can lead to activation of stemness-controlling transcription factors. Additionally, the cell surface expression of chemokine receptors provides a unique therapeutic target to disrupt signaling pathways that control the expression of master regulator transcription factors and the TIC phenotype. This review summarizes the master regulator transcription factors known to dictate the TIC phenotype, along with the complex signaling pathways that can mediate their expression and the chemokine receptors that are most upstream of this phenotype.
RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.
Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA¹. The broad genomic complexity caused by CIN is a hallmark of cancer²; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.
Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7–59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7–49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6–16.5) and 2.4% (95% CI, 0.1–12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients’ selection for pembrolizumab treatment. In a trial of patients with soft-tissue sarcomas, clinical outcome measures following anti-PD-1 treatment were better in a cohort prospectively selected for the presence of intratumoral tertiary lymphoid structures than in other cohorts where most patients lacked these structures.
Tumor-infiltrating lymphocytes (TILs) are critical in the elimination of cancer cells, a concept highlighted by recent advances in cancer immunotherapy. Significant evidence reveals that their organization in tertiary lymphoid structures together with specific subpopulation composition/balances stimulates cellular crosstalk and anti-tumor immunity in patients.
Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject, and transplant organelles from and into living cells with subcellular spatial resolution. The technology combines atomic force microscopy, optical microscopy, and nanofluidics to achieve force and volume control with real-time inspection. We developed dedicated probes that allow minimally invasive entry into cells and optimized fluid flow to extract specific organelles. When extracting single or a defined number of mitochondria, their morphology transforms into a pearls-on-a-string phenotype due to locally applied fluidic forces. We show that the induced transition is calcium independent and results in isolated, intact mitochondria. Upon cell-to-cell transplantation, the transferred mitochondria fuse to the host cells mitochondrial network. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed monitoring of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 minutes after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, donor mitochondrial DNA (mtDNA) was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle physiology and homeostasis, but also for therapy, mechanobiology, and synthetic biology.
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.
Background Patterns of metastasis in cancer are increasingly relevant to prognostication and treatment planning but have historically been documented by means of autopsy series. Purpose To show the feasibility of using natural language processing (NLP) to gather accurate data from radiology reports for assessing spatial and temporal patterns of metastatic spread in a large patient cohort. Materials and Methods In this retrospective longitudinal study, consecutive patients who underwent CT from July 2009 to April 2019 and whose CT reports followed a departmental structured template were included. Three radiologists manually curated a sample of 2219 reports for the presence or absence of metastases across 13 organs; these manually curated reports were used to develop three NLP models with an 80%-20% split for training and test sets. A separate random sample of 448 manually curated reports was used for validation. Model performance was measured by accuracy, precision, and recall for each organ. The best-performing NLP model was used to generate a final database of metastatic disease across all patients. For each cancer type, statistical descriptive reports were provided by analyzing the frequencies of metastatic disease at the report and patient levels. Results In 91 665 patients (mean age ± standard deviation, 61 years ± 15; 46 939 women), 387 359 reports were labeled. The best-performing NLP model achieved accuracies from 90% to 99% across all organs. Metastases were most frequently reported in abdominopelvic (23.6% of all reports) and thoracic (17.6%) nodes, followed by lungs (14.7%), liver (13.7%), and bones (9.9%). Metastatic disease tropism is distinct among common cancers, with the most common first site being bones in prostate and breast cancers and liver among pancreatic and colorectal cancers. Conclusion Natural language processing may be applied to cancer patients' CT reports to generate a large database of metastatic phenotypes. Such a database could be combined with genomic studies and used to explore prognostic imaging phenotypes with relevance to treatment planning. © RSNA, 2021 Online supplemental material is available for this article.
Ecological fitness is the ability of individuals in a population to survive and reproduce. Individuals with increased fitness are better equipped to withstand the selective pressures of their environments. This paradigm pertains to all organismal life as we know it; however, it is also becoming increasingly clear that within multicellular organisms exist highly complex, competitive, and cooperative populations of cells under many of the same ecological and evolutionary constraints as populations of individuals in nature. In this review I discuss the parallels between populations of cancer cells and populations of individuals in the wild, highlighting how individuals in either context are constrained by their environments to converge on a small number of critical phenotypes to ensure survival and future reproductive success. I argue that the hallmarks of cancer can be distilled into key phenotypes necessary for cancer cell fitness: survival and reproduction. I posit that for therapeutic strategies to be maximally beneficial, they should seek to subvert these ecologically driven phenotypic responses.
Most physical and other natural systems are complex entities that are composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws that relate an observable quantity to a measure of the size of the system. Here, we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, owing to evolutionary dynamics, that leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of patients with cancer. To explain our observations we tested complex, biologically inspired mathematical models that describe the key processes that govern tumour growth. Our models predict that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws that we identified allowed us to define a set of metabolic metrics with prognostic value, which adds clinical utility to our findings. The authors investigate the relationship between the volume of malignant tumours and their metabolic processes using a large dataset of patients with cancer. They find that cancers follow a superlinear metabolic scaling law, which implies that the proliferation of cancer cells accelerates with increasing volume.
Significance
Poorly irrigated tumors exhaust nutrients from their environment. On the other hand, innate immune cells, such as neutrophils and macrophages, have been frequently shown to infiltrate tumors and promote an immunosuppressive environment. Our results show that, when nutrients are low, tumor cells secrete factors related to wound healing that stimulate endothelial cells and attract innate immune cells. This suggests that targeting signals elicited by metabolic stress may help the immune system target malignant cells and that metabolites regulate the communication between immune and tumor cells also through modulation of peptidic signals.
Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC is an essential component of a cytoplasmic protein complex that targets β-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous β-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/β-catenin signaling such that in response to Wnt, the β-catenin destruction complex: (1) maintains composition and binding to β-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization.
Non Hodgkin lymphoma, predominantly Diffuse Large B-cell Lymphoma (DLBCL) has been reported to have a significant association with Hepatitis B virus (HBV). We investigated the presence of different gene segments of HBV in plasma, B-cells and tumor tissues from DLBCL patients and explored the genetic variability of HBV within and across different compartments in a host using Next Generation Sequencing. Despite all 40 patients being HBV seronegative, 68% showed evidence of occult HBV. Sequencing of these gene segments revealed inter-compartment viral variants in 26% of them, each with at least one non-synonymous mutation. Between compartments, core gene variants revealed Arg94Leu, Glu86Arg and Ser41Thr while X gene variants revealed Phe73Val, Ala44Val, Ser146Ala and Ser147Pro. In tumor compartments per se, several mis-sense mutations were detected, notably the classic T1762A/A1764G mutation in the basal core promoter. In addition, a virus surface antigen mis-sense mutation resulting in M125T was detected in all the samples and could account for surface antigen negativity and occult HBV status. It would be interesting to further explore if a temporal accumulation of viral variants within a favored niche, like patients’ lymphocytes, could bestow survival advantage to the virus, and if certain pro-oncogenic HBV variants could drive lymphomagenesis in DLBCL.
Significance
In evolutionary biology, it is generally assumed that evolution occurs in the weak mutation limit, that is, the frequency of multiple mutations simultaneously occurring in the same genome and the same generation is negligible. We employ mathematical modeling to show that, although under the typical parameter values of the evolutionary process the probability of multimutational leaps is indeed low, they might become substantially more likely under stress, when the mutation rate is dramatically elevated. We hypothesize that stress-induced mutagenesis in microbes is an evolvable adaptive strategy. Multimutational leaps might matter also in other cases of substantially increased mutation rate, such as growing tumors or evolution of primordial replicators.
The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non-transcriptional functions fighting back against genomic instability.
Background/aims:
Radiotherapy is applied to patients with inoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistance functions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism of radioresistance regulated by surfactant protein B (SP-B).
Methods:
To investigate the role of SP-B in radioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response to ionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines. Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway. The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection of CM.
Results:
In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signaling and decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CM from irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, and increased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograft model.
Conclusion:
Our results revealed that down-regulation of SP-B was involved in the radiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressor of NSCLC progression.
Despite certain quantum concepts, such as superposition states, entanglement, 'spooky action at a distance' and tunnelling through insulating walls, being somewhat counterintuitive, they are no doubt extremely useful constructs in theoretical and experimental physics. More uncertain, however, is whether or not these concepts are fundamental to biology and living processes. Of course, at the fundamental level all things are quantum, because all things are built from the quantized states and rules that govern atoms. But when does the quantum mechanical toolkit become the best tool for the job This review looks at four areas of 'quantum effects in biology'. These are biosystems that are very diverse in detail but possess some commonality. They are all (i) effects in biology: rates of a signal (or information) that can be calculated from a form of the 'golden rule' and (ii) they are all protein-pigment (or ligand) complex systems. It is shown, beginning with the rate equation, that all these systems may contain some degree of quantum effect, and where experimental evidence is available, it is explored to determine how the quantum analysis AIDS in understanding of the process. © 2017 The Author(s) Published by the Royal Society. All rights reserved.
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution, most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (~3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predicted the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The anti-tumor effects of chemotherapies can in part be due to induction of genomic instability and increased passenger load.
Molecular imaging continues to influence every aspect of cancer care including detection, diagnosis, staging and therapy response assessment. Recent advances in the understanding of cancer biology have prompted the introduction of new targeted therapy approaches. Precision medicine in oncology has led to rapid advances and novel approaches optimizing the use of imaging modalities in cancer care, research and development. This article focuses on the concept of targeted therapy in cancer and the challenges that exist for molecular imaging in cancer care.
Multiple theories of aging (e.g., free radical, error catastrophe, mitochondrial) are complementary but fail to provide adequate models that comprehensively predict lifelong aging processes and that are valid across species. Hayflick (PLoS Genet 3(12):2351–2354, 2007) described six universal characteristics of aging that focus upon post-reproductive molecular entropy. Here we present a thermodynamic potential model of aging in which the energetic and topological properties of the mitochondrion drive functional and structural stabilities within living systems. Using multivariate regressions of physiological assessments from the National Health and Nutrition Examination Survey, VO2 max consistently declined with age regardless of gender or race, although it had a significantly greater decline for African American females. Percent fat (negative), hematocrit (negative), and urine creatinine (negative) were strongly and significantly associated with VO2 max and male aging, although cholesterol (positive) was an additional factor for African American males. Bioenergetic measures such as VO2 max can be useful for physical assessments to promote healthy aging.
The biological effects of high-gradient magnetic fields (HGMFs) have steadily gained the increased attention of researchers from different disciplines, such as cell biology, cell therapy, targeted stem cell delivery and nanomedicine. We present a theoretical framework towards a fundamental understanding of the effects of HGMFs on intracellular processes, highlighting new directions for the study of living cell machinery: changing the probability of ion-channel on/off switching events by membrane magneto-mechanical stress, suppression of cell growth by magnetic pressure, magnetically induced cell division and cell reprograming, and forced migration of membrane receptor proteins. By deriving a generalized form for the Nernst equation, we find that a relatively small magnetic field (approximately 1 T) with a large gradient (up to 1 GT/m) can significantly change the membrane potential of the cell and thus have a significant impact on not only the properties and biological functionality of cells but also cell fate.
Evolution by natural selection is the conceptual foundation for nearly every branch of
biology and increasingly also for biomedicine and medical research. In cancer biology,
evolution explains how populations of cells in tumors change over time. It is a fundamental
question whether this evolutionary process is driven primarily by natural selection and
adaptation or by other evolutionary processes such as founder effects and drift. In cancer
biology, as in organismal evolutionary biology, there is controversy about this question and
also about the use of adaptation through natural selection as a guiding framework for research.
In this review, we discuss the differences and similarities between evolution among
somatic cells versus evolution among organisms. We review what is known about the parameters
and rate of evolution in neoplasms, aswell as evidence for adaptation.We conclude
that adaptation is a useful framework that accurately explains the defining characteristics of
cancer. Further, convergent evolution through natural selection provides the only satisfying
explanation both for howa group of diverse pathologies have enough in common to usefully
share the descriptive label of “cancer” and for why this convergent condition becomes lifethreatening.
Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.Oncogene advance online publication, 12 September 2016; doi:10.1038/onc.2016.304.
The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.
Background
Syncytin-1, a cell membrane-localizing fusogen, is abnormally expressed in several cancers, including endometrial cancer, breast cancer, and leukemia. Although abnormal syncytin-1 expression has been detected in two-thirds of leukemia blood samples, its expression profile in acute leukemia patients has not yet been analyzed.
Material/Methods
Bone marrow samples from 50 acute myelogenous leukemia (AML) cases and 14 B-cell acute lymphocytic leukemia (B-cell ALL) patients were subjected to flow cytometry to assess leukocyte type distributions and leukocytic syncytin-1 surface expression. RT-PCR was applied to assess leukocytic syncytin-1 mRNA expression. Statistical analysis was applied to compare syncytin-1 expression between AML and B-cell ALL patients across blasts, granulocytes, lymphocytes, and monocytes as well as to determine clinical factors statistically associated with changes in syncytin-1 expression.
Results
The leukocyte type distributions of the AML and B-cell ALL cohorts highly overlapped, with an observable difference in blast distribution between the 2 cohorts. The AML cohort displayed significantly greater syncytin-1 surface and mRNA expression (p<0.05). Syncytin-1 surface and mRNA expression was significantly increased across all 4 leukocyte types (p<0.05). The percentage of syncytin-1-expressing blasts was significantly greater in AML patients (p<0.05), with blasts showing the largest fold-change in syncytin-1 expression (p<0.05). M5, M5a, and M5b AML patients displayed significantly higher syncytin-1 surface expression relative to all other AML French-American-British (FAB) classifications (p<0.05).
Conclusions
These findings suggest leukocytic syncytin-1 expression may play a role in the development and/or maintenance of the AML phenotype and the acute monocytic leukemia phenotype in particular.
The meaning and influence of light to biomolecular interactions, and consequently to health, has been analyzed using the Resonant Recognition Model (RRM). The RRM proposes that biological processes/interactions are based on electromagnetic resonances between interacting biomolecules at specific electromagnetic frequencies within the infra-red, visible and ultraviolet frequency ranges, where each interaction can be identified by the certain frequency critical for resonant activation of specific biological activities of proteins and DNA. We found that: (1) the various biological interactions could be grouped according to their resonant frequency into super families of these functions, enabling simpler analyses of these interactions and consequently analyses of influence of electromagnetic frequencies to health; (2) the RRM spectrum of all analyzed biological functions/interactions is the same as the spectrum of the sun light on the Earth, which is in accordance with fact that life is sustained by the sun light; (3) the water is transparent to RRM frequencies, enabling proteins and DNA to interact without loss of energy; (4) the spectrum of some artificial sources of light, as opposed to the sun light, do not cover the whole RRM spectrum, causing concerns for disturbance to some biological functions and consequently we speculate that it can influence health.
The evolutionarily novel genes originated through different molecular mechanisms are expressed in tumors. Sometimes the expression of evolutionarily novel genes in tumors is highly specific. Moreover positive selection of many human tumor-related genes in primate lineage suggests their involvement in the origin of new functions beneficial to organisms.
It is suggested to consider the expression of evolutionarily young or novel genes in tumors as a new biological phenomenon, a phenomenon of TSEEN (tumor specifically expressed, evolutionarily novel) genes.
We calculate the high and low scale threshold corrections to the D=6 proton decay mode in supersymmetric SU(5) grand unified theories with higher-dimensional representation Higgs multiplets. In particular, we focus on a missing-partner model in which the grand unified group is spontaneously broken by the 75-dimensional Higgs multiplet and the doublet-triplet splitting problem is solved. We find that in the missing-partner model the D=6 proton decay rate gets suppressed by about 60%, mainly due to the threshold effect at the GUT scale, while the SUSY-scale threshold corrections are found to be less prominent when sfermions are heavy.
Poor differentiation is an important hallmark of cancer cells, and differentiation therapy holds great promise for cancer treatment. The restoration of IkB kinase α (IKKα) leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity. The findings by Yan et al. validate the polycomb protein enhancer of zeste homologue 2 (EZH2) as a target for intervention.
Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4⁺ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFβ and TGFβ-mediated fibroblast activation, indicating that TGFβ-receptor loss on cancer cells increased TGFβ bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME.
We previously demonstrated that tumor infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL and TIL-B, co-localizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFNγ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B in active germinal centers) and cytotoxic (GZMB+CD8+ and GZMB+CD68+ TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a CD25+CXCR5+GARP+FOXP3+ phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a GARP-associated TGFβ-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and CD8+ TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.
It has long been recognized that cancer onset and progression represent a type of reversion to an ancestral quasi‐unicellular phenotype. This general concept has been refined into the atavistic model of cancer that attempts to provide a quantitative analysis and testable predictions based on genomic data. Over the past decade, support for the multicellular‐to‐unicellular reversion predicted by the atavism model has come from phylostratigraphy. Here, we propose that cancer onset and progression involve more than a one‐off multicellular‐to‐unicellular reversion, and are better described as a series of reversionary transitions. We make new predictions based on the chronology of the unicellular‐eukaryote‐to‐multicellular‐eukaryote transition. We also make new predictions based on three other evolutionary transitions that occurred in our lineage: eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity. We propose several modifications to current phylostratigraphy to improve age resolution to test these predictions.
Context.—Many studies have addressed metastatic patterns seen among various cancers. No recent studies, however, provide quantitative analyses of such patterns arising from a broad range of cancers based primarily on postmortem tissue analyses.
Objective.—To provide a quantitative description of metastatic patterns among different primary cancers based on data obtained from a large, focused autopsy study.
Design.—Review of data from 3827 autopsies, performed between 1914 and 1943 on patients from 5 affiliated medical centers, comprising 41 different primary cancers and 30 different metastatic sites.
Results.—Testicular cancers were most likely to metastasize (5.8 metastases per primary cancer), whereas duodenal cancers were least likely to do so (0.6 metastases per primary cancer). Preferred metastatic sites varied among the primary cancers analyzed. Overall, regional lymph nodes were the most common metastatic target (20.6% of total), whereas testes were the least common (0.1% of total).
Conclusions.—Not surprisingly, different primary cancers tended to metastasize, with differing frequencies, to different sites. These varying metastatic patterns might be helpful in deducing the origins of cancers whose primary sites are unclear at presentation.
Significance
Genomic instability is characteristic of the majority of cancers. It includes changes of copy numbers of genes and chromosomes during diverse cell processes, such as genome replication. Genomic instability is a strong biomarker of poor prognosis. An analysis of DNA copy numbers in human tumors across different cancers reveals an instability in an energetic sense: The free energy of the distribution of gene loci copy numbers in each tumor is found to be a monotonically increasing and universal function of the mean chromosome ploidy in that tumor. This relates the biological (genomic instability) with the physicochemical stability criterion. The analysis also shows that it is energetically more favorable for genome doubling to occur from a not-already-fragmented genome.
Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that form within nonlymphoid tissue. They share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell region. TLS have been described in several types of cancers and are usually associated with positive patient outcomes. However, TLS differ vastly in cellular composition and location within tissue types. In this review, we discuss factors confounding the interpretation of the evidence for a prognostic role for TLS in cancer and frame these factors in the context of translation to regular clinical use.
Although tumours initiate from oncogenic changes in a cancer cell, subsequent tumour progression and therapeutic response depend on interactions between the cancer cells and the tumour microenvironment (TME). The primary monocilium, or cilium, provides a spatially localized platform for signalling by Hedgehog, Notch, WNT and some receptor tyrosine kinase pathways and mechanosensation. Changes in ciliation of cancer cells and/or cells of the TME during tumour development enforce asymmetric intercellular signalling in the TME. Growing evidence indicates that some oncogenic signalling pathways as well as some targeted anticancer therapies induce ciliation, while others repress it. The links between the genomic profile of cancer cells, drug treatment and ciliary signalling in the TME likely affect tumour growth and therapeutic response.
RAS
genes (HRAS,KRAS, andNRAS) comprise the most frequently mutated oncogene family in human cancer. With the highestRASmutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered. With the KRAS isoform mutated in 84% of allRAS-mutant cancers, we focus on KRAS. With a near 100%KRASmutation frequency, pancreatic ductal adenocarcinoma (PDAC) is considered the most RAS-addicted of all cancers. We review the role of KRAS as a driver and therapeutic target in PDAC.
Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.Cell Research advance online publication 23 December 2016; doi:10.1038/cr.2016.153.
The spread of cancer from a primary tumor to distant organ sites is the most devastating aspect of malignancy. Dissemination to specific organs depends upon blood flow patterns and characteristics of the distant organ environment, such as the vascular architecture, stromal cell content, and the biochemical milieu of growth factors, signaling molecules, and metabolic substrates, which can be permissive or antagonistic to metastatic colonization. Metastatic tumor cells possess intrinsic cellular properties selected for adaptation to specific organ environments, where they co-opt growth and survival signals, undergo metabolic reprogramming, and subvert resident stromal cell activities to promote extravasation, immune evasion, angiogenesis, and overt metastatic growth. Recent work and new experimental models of metastatic organotropism are uncovering crucial details of how malignant cells metastasize to specific tissues, revealing key mediators that prepare metastatic niches in specific organs and identifying new targets that offer attractive options for therapeutic intervention. Expected final online publication date for the Annual Review of Cancer Biology Volume 1 is March 04, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer related mortality. Once established, metastasis is devastating, yet only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ specific and consequently demand distinct mechanisms for metastatic colonization. Here we review the metastatic traits that allow cancer cells to colonize distinct organ sites.