[show abstract][hide abstract] ABSTRACT: The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
[show abstract][hide abstract] ABSTRACT: Background:In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI.Methods:We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells.Results:In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours.Conclusion:Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.British Journal of Cancer advance online publication, 1 October 2013; doi:10.1038/bjc.2013.565 www.bjcancer.com.
British Journal of Cancer 10/2013; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor microenvironment inflammatory cells play a major role in cancer progression. Among these, the Tumor Associated Macrophages (TAMs) infiltration depends on the kind of chemokine, cytokines and growth factors secreted by the tumor cells and by the stroma in response to the cancer invasion. TAMs have been found to promote anti-tumor response in early stages and to stimulate neovascularization and metastases in advanced disease. In the microenvironment chemo-attractants of many human cancers, MIF and VEGF correlate with an increased TAMs recruitment. In addition, MIF enhances tumor cells metastases by modulating the immune responses and by promoting the angiogenesis related to VEGF. On the contrary the inhibition of MIF can lead to cell cycle arrest and apoptosis. Some chemokines (e.g. CXCL12, CXCL11, CXCL8) and their receptors, thanks to their ability to modulate migration and proliferation, are involved in the angiogenetic process. In this study we compared the expression of MIF mRNA with VEGF mRNA expression and with mRNA expression of other chemokines related to neo-angiogenesis, such as CXCL12, CXCL11, CXCL8 and CXCR4, in human endometrial cancer tissue (EC) and normal endometrium (NE). Fresh samples of EC tissue and NE were extracted from 15 patients with FIGO stage I-III undergoing primary surgery. Some of the tissue was sent for histology and part of it was treated with RNA later and stored at -80°C. Four patients dropped out. A significant up-regulation of MIF mRNA in EC tissue versus NE samples (P=0.01) was observed in all 11 patients. The MIF mRNA over-expression was coincident with a VEGF mRNA overexpression in 54% of patients (P=NS). MIF mRNA was inversely related to CXCL12 mRNA expression (P=0.01). MIF over-expression was significantly related to low grading G1-2 (P=0.01), endometrial type I (P=0.05), no lymphovascular spaces invasion (P=0.01) and 3years DFS (P=0.01). As reported in previous studies on patients with breast cancer, our data suggest that the up-regulation of MIF in patients with endometrial cancer might be related to the inhibition of distant and lymphatic spread.
[show abstract][hide abstract] ABSTRACT: Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis. We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes). The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.
[show abstract][hide abstract] ABSTRACT: Inflammation is now a well-recognized hallmark of cancer progression. Tumor-associated macrophages (TAMs) are one of the major inflammatory cells that infiltrate murine and human tumors. While epidemiological studies indicate a clear correlation between TAM density and poor prognosis in a number of human cancers, transgenic studies and transcriptome profiling of TAMs in mice have established their crucial role in cancer progression. In fact, TAMs affect diverse aspects of cancer progression including tumor cell growth and survival, invasion, metastasis, angiogenesis, inflammation, and immunoregulation. New evidences have extended the repertoire of these cells to other tumor promoting activities like interactions with cancer stem cells, response to chemotherapy, and tumor relapse. These findings have triggered efforts to target TAMs and their associated molecules to modulate tumor progression. In particular, "re-education" to activate their anti-tumor potential or elimination of tumor promoting TAMs are strategies undergoing preclinical and clinical evaluation. Proof-of-principle studies indicate that TAM-centered therapeutic strategies may contribute to cancer therapy.
Seminars in Immunopathology 05/2013; · 5.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aim: Recent experimental studies have suggested that chemokines, a subclass of chemoattractant cytokines which play an important role in regulating leukocyte migration and intercellular communication, participate in brain responses of traumatic injury. Fractalkine (CX3CL1) is a peculiar chemokine, the only one with a CX3C motif, existing both as a soluble and a membrane-anchored molecule. In the brain, Fractalkine has been suggested to have a role in neuroprotection under experimental conditions of brain injury. Methods: Eighteen human brain samples were obtained during surgery of decompressive craniotomy for severe traumatic brain injury (TBI) or after spontaneous intracranial haemorrhage (ICH). Five normal brain samples were obtained during surgery for unruptured intracranial aneurysms (standard gyrectomy). Immunohistochemistry of formalin fixed and paraffin embedded tissues was performed in order to verify the expression of fractalkine and its receptor (CX3CR1). The values of chemokine and receptor expression were correlated with the clinical parameters of the patients. Results: The chemokine fractalkine was significantly upregulated in the neural compartment after brain injury, compared to normal brain samples. Intensity scores were significantly higher when the interval between injury and surgery was >5 h, (P=0.015). In the glial compartment, Fractalkine expression was significantly associated with less severe clinical conditions and lower intracranial pressure at surgery (P=0.014). Expression of the receptor CX3CR1 was detected, at low intensity, on both glial and neurons. Higher expression in neurons was associated with better clinical conditions (Glasgow score) of patients at admission (P=0.037). Conclusion: The results of this study highlights for the first time that fractalkine and its receptor CX3CR1 are expressed in the human brain after TBI and ICH and may be involved in the limitation of tissue damage.
Journal of neurosurgical sciences 03/2013; 57(1):55-62. · 0.53 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
Cancer cell 02/2013; 23(2):249-62. · 25.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.
Journal of Biological Chemistry 04/2012; 287(26):21904-13. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2(+) monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti-cancer treatments.
[show abstract][hide abstract] ABSTRACT: Over the last decade it has been established that cancer-associated inflammation affects many aspects of malignancy and in particular endorses tumor cell survival, proliferation and distant spread. Chemokines and their receptors are major players of the cancerrelated inflammation. Our understanding of the chemokine role in tumor biology now ranges from their ability to recruit blood leukocytes within tumors, to direct effects on cancer cell survival, metastatization and regulation of angiogenesis. Chemokines and their receptors are expressed in human pancreatic adenocarcinoma and are involved in its malignant behavior. Notably, the receptor CX3CR1 favors tumor perineural tropism which is typical of this neoplasm and is associated with early recurrence after surgery and with poor patient prognosis.
Current pharmaceutical design 02/2012; 18(17):2432-8. · 4.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Experimental and epidemiological studies indicate a strong link between chronic inflammation and tumor progression. Human colorectal cancer (CRC), a major cause of cancer-related death in Western countries, represents a paradigm for this link. Key features of cancer-related inflammation in CRC are the activation of transcription factors (e.g. NF-κB, STAT3), the expression of inflammatory cytokines and chemokines (e.g. TNFα, IL-6, CCL2, CXCL8) as well as a prominent leukocyte infiltrate. While considerable evidence indicates that the presence of lymphocytes of adaptive immunity may positively influence patient survival and clinical outcome in CRC, the role of tumor-associated macrophages (TAM) and of other lymphoid populations (e.g. Th17, Treg) is still unclear. In this review we will summarize the different and controversial effects that TAM play in CRC-related inflammation and progression of disease. The characterization of the most relevant inflammatory pathways in CRC is instrumental for the identification of new target molecules that could lead to improved diagnosis and treatment.
[show abstract][hide abstract] ABSTRACT: Different types of cancer take advantage of inflammatory components to improve their life-span in the organs. A sustenance of growth factors and cytokines (e.g. interleukin (IL)-1, tumor necrosis factor, IL-6, vascular endothelial growth factor) supports malignant cell progression and contributes to suppress the body immune defense. Strategies to modulate the host micro-environment offer new approaches for anti-cancer therapies. For these reasons new molecules with anti-tumor and anti-inflammatory features (e.g. trabectedin) are looked at with new eyes in the light of the crucial link between inflammation and cancer.
Annals of medicine 07/2011; 43(8):581-93. · 3.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression.
[show abstract][hide abstract] ABSTRACT: Accumulating evidence shows that chronic inflammation is associated to increased risk of cancer. An inflammatory component is present also in the microenvironment of tumours epidemiologically unrelated to inflammation. Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. Pathways linking inflammation and cancer have been identified: an intrinsic one (driven by genetic events that cause neoplasia) and an extrinsic one (driven by inflammatory conditions which predispose to cancer). Smouldering inflammation is a component of the tumour microenvironment and is a recognized hallmark of cancer. Key orchestrators at the intersection of the intrinsic and extrinsic pathways include transcription factors (e.g. Nuclear Factor kappa-B, NFKB) that modulate the inflammatory response through soluble mediators (cytokines, chemokines) and cellular components (e.g. tumor-associated macrophages), promoting tumorigenesis. NFKB aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immunity, and alters responses to hormones and chemotherapeutic agents. Emerging evidence also suggests that persistent inflammation promotes genetic instability. Thus, cancer-related inflammation represents a target for innovative diagnostic and therapeutic strategies.
[show abstract][hide abstract] ABSTRACT: Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.
[show abstract][hide abstract] ABSTRACT: Smoldering, nonresolving inflammation is part of the tumor microenvironment (Balkwill and Mantovani 2001; Coussens and Werb 2002; Mantovani et al. 2008a). Inflammatory cells and mediators are present in the microenvironment of cancers epidemiologically related or unrelated
to inflammatory or infectious conditions. Leukocyte infiltration and the presence of soluble mediators such as cytokines,
and chemokines are key characteristics of CRI. Conditions predisposing to cancer (e.g., inflammatory bowel disease, IBD) or genetic events that cause neoplastic transformation
orchestrate the construction of an inflammatory microenvironment. Indeed, alterations of oncogenes drive the production of
inflammatory mediators. Thus, an intrinsic pathway of inflammation (driven in tumor cells), as well as an extrinsic pathway
driven by chronic inflammatory conditions have been identified, both of which contribute to tumor progression (Mantovani et
[show abstract][hide abstract] ABSTRACT: Human gliomas represent an unmet clinical challenge as nearly two-thirds of them are highly malignant lesions with fast progression, resistance to treatment and poor prognosis. The most severe form, the glioblastoma multiforme, is characterised by a marked and diffuse infiltration through the normal brain parenchyma. Given the multiple effects of chemokines on tumour progression, aim of this study was to analyse the expression of the chemokine CX3CL1 and of its specific receptor CX3CR1 in 36 human surgical glioma samples, with different degrees of histological malignancy and in glioblastoma-derived neurospheres. Herein we show that both ligand and receptor are expressed at the mRNA and protein levels in most specimens (31/36). While receptor expression was similarly detected in low or high grade tumours, the uppermost scores of CX3CL1 were found in grades III-IV tumours: oligodendrogliomas, anaplastic astrocytomas and glioblastomas. Accordingly, the expression of CX3CL1 was inversely correlated with patient overall survival (p = 0.01). Glioblastoma-derived neurospheres, containing a mixed population of stem and progenitor cells, were positive for both CX3CR1 and for the membrane-bound chemokine, which was further up-regulated and secreted after TNF-IFNγ stimulation. Confocal microscopy of 3D neurospheres showed that the ligand was primarily expressed in the outer layer cells, with points of co-localisation with CX3CR1, indicating that this ligand-receptor pair may have important intercellular adhesive functions. The high expression of CXC3L1 in the most severe forms of gliomas suggests the involvement of this chemokine and its receptor in the malignant behaviour of these tumours.
European journal of cancer (Oxford, England: 1990) 12/2010; 46(18):3383-92. · 4.12 Impact Factor