Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer

Colorectal cancer (CRC) progression and eventually metastasis is directed in many aspects by a circuitous ecosystem consisting of an extracellular matrix scaffold populated by cancer-associated fibroblasts (CAFs), endothelial cells, and diverse immune cells. CAFs are recruited from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors. CAFs are highly abundant in CRC. In this review, we apply the metastasis-promoting communication of colorectal CAFs to 10 cancer hallmarks described by Hanahan andWeinberg. CAFs influence innate and adaptive tumor immune responses. Using datasets from previously published work, we re-explore the potential messages implicated in this process. Fibroblasts present in metastasis (metastasis-associated fibroblasts) from CRC may have other characteristics and functional roles than CAFs in the primary tumor. Since CAFs connect metastasis-promoting communication, CAF markers are potential prognostic biomarkers. CAFs and their products are possible targets for novel therapeutic strategies

TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer

Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

Tumours are complex systems with dynamic interactions between tumour cells, nontumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME’s cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal–cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs “re-education” and/or targeting tumour progression inhibition.Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía and European Regional Development Fund (ERDF), ref. P18-FR-2470,Ministry of Science, Innovation and Universities (ref. RTI2018-101309-B-C22)Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963

Cell-cell interactions in the gastrointestinal tumour-microenvironment

The tumour-microenvironment consists of malignant epithelial cells, surrounding cancer associated (myo-)fibroblasts, endothelial cells creating the tumours__ vasculature system and infiltrating inflammatory cells. In this thesis we have studied how interactions between these cell types contribute to the initiation, progression and metastasis formation in gastrointestinal cancers. We have focused on how the availability of two important growth factors (Transforming Growth Factor-_ and Vascular Endothelial Growth Factor) in tumour angiogenesis and myofibroblasts differentiation is regulated by interactions between different cell types. First we revealed that active TGF-_1 levels are strongly increased in gastric and colorectal carcinomas and that they are indicative for the survival of these patients. In premalignant lesions increased activation is not yet observed. In addition we show that active TGF-_ levels are correlated with the number of myofibroblasts in colorectal carcinomas. Furthermore we reveal that interaction between colon cancer cells and cancer associated fibroblasts leads to increased TGF-_ activation, subsequent myofibroblast trans-differentiation accompanied by upregulation of TGF-_ expression and increased matrix metalloproteinase (MMP) secretion. To further evaluate how MMPs regulate tumour progression we have investigated their role in tumour-angiogenesis. We show that MMP-9, derived from tumour-infiltrating neutrophils, contributes to the angiogenic switch, by releasing tumour cell derived VEGF from the extracellular matrix. Finally, we show that tumour-angiogenesis requires endothelial MMP-7 expression and is regulated by MMP-14 dependent cleavage of the TGF-_ co-receptor endoglin on angiogenic endothelial cells. In conclusion, these studies show that interaction between tumour cells, fibroblasts and endothelial cells are important for the generation of myofibroblasts by TGF-_ activation and for the initiation of angiogenesis by regulating VEGF release. These data further validate the tumour-microenvironment as an important therapeutic target.UBL - phd migration 201

Galectins: Multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment

Tumor cells corrupt surrounding normal cells instructing them to support proliferative, pro-angiogenic and immunosuppressive networks that favor tumorigenesis and metastasis. This dynamic cross-talk is sustained by a range of intracellular signals and extracellular mediators produced by both tumoral and non-tumoral cells. Galectins –whether secreted or intracellularly expressed– play central roles in the tumorigenic process by delivering regulatory signals that contribute to reprogram fibroblasts, endothelial and immune cell programs. Through glycosylation-dependent or independent mechanisms, these endogenous lectins control a variety of cellular events leading to tumor cell proliferation, survival, migration, inflammation, angiogenesis and immune escape. Here we discuss the role of galectin-driven pathways, particularly those activated in non-tumoral stromal cells, in modulating tumor progression.Fil: Elola, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Ferragut, Fatima Eneida del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bracalente, María Candelaria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Fibroblasts in the Tumor Microenvironment : Shield or Spear?

Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-cell contact, paracrine signaling by soluble factors, and ECM integrity. The loss of such suppressive functions is an inherent step in tumor progression. A tumor cell-induced switch of normal fibroblasts into cancer-associated fibroblasts (CAFs), in turn, triggers a range of pro-tumorigenic signals accompanied by distraction of the normal tissue architecture, thus creating an optimal niche for cancer cells to grow extensively. To further support tumor progression and metastasis, CAFs secrete factors such as ECM remodeling enzymes that further modify the tumor microenvironment in combination with the altered adhesive forces and cell-cell interactions. These paradoxical tumor suppressive and promoting actions of fibroblasts are the focus of this review, highlighting the heterogenic molecular properties of both normal and cancer-associated fibroblasts, as well as their main mechanisms of action, including the emerging impact on immunomodulation and different therapy responses.Peer reviewe

Productive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis

Most ovarian cancer patients present with disseminated disease at the time of their diagnosis, which is one of the main reasons for their poor prognosis. Metastasis is a multi-step process and a clear understanding of the mechanism of regulation of these steps remains elusive. Productive reciprocal interactions between the metastasizing ovarian cancer cells and the microenvironment of the metastatic site or the tumor microenvironment play an important role in the successful establishment of metastasis. Much progress has been made in the recent past in our understanding of such interactions and the role of the cellular and acellular components of the microenvironment in establishing the metastatic tumors. This review will outline the role of the microenvironmental components of the ovarian cancer metastatic niche and their role in helping establish the metastatic tumors. Special emphasis will be given to the mesothelial cells, which are the first cells encountered by the cancer cells at the site of metastasis

Radiation Effects on Mesenchymal Stem Cells in a Model of Fibrosarcoma

Background: Radiotherapy is a mainstay of sarcoma treatment, but can cause fibrosis, characterized by production of extra-cellular matrix proteins such as collagen by cancer-associated fibroblasts (CAFs) in the cancer stroma and surrounding normal tissues, which makes tumours more aggressive and resistant to further treatment. Mesenchymal stem cells (MSCs) can be recruited to irradiated tumours and can differentiate into CAF-like cells but the mechanisms of these effects remain unclear. Aim: Determine the mechanisms of radiation effects on the recruitment of MSCs to tumours and their differentiation into CAF-like cells. Methods: Mouse MSCs were irradiated directly or exposed to irradiated mouse fibrosarcoma cells (FS120 or FS188) or their conditioned media (CM) and/or irradiated endothelial cells. Expression of CAF/fibrosis markers (collagen, fibronectin, PDGF receptor-β and α-SMA) by MSCs was assessed 3-4 days’ post radiation. Trans-well migration assays were also performed. Candidate proteins were investigated for their ability to stimulate migration and maturation of MSCs to CAF-like cells and for the ability of radiation to stimulate their production in fibrosarcoma cells. Irradiated FS120 and FS188 solid tumours were analysed for collagen, using Masson’s trichrome staining, and α-SMA using IHC and immunofluorescence. Results: Direct irradiation of MSCs had limited effects on their expression of CAF markers and migration, but exposure to irradiated tumour cells or CM and/or endothelial cells increased these effects. Candidate proteins TGF-β1, MCP-1, and SDF-1α all significantly enhanced the migration of MSCs, and radiation increased their production in fibrosarcoma cells. FS188 cells produced more MCP-1 than FS120 cells and FS188 and FS120 cells and their CM increased MSC migration in a radiation-dependent manner. Migration could be at least partially blocked by an MCP-1 blocking antibody. MSC expression of the MCP-1 receptor, CCR2, was increased after exposure to irradiated FS188 cells or their CM. In vivo, irradiated fibrosarcomas showed significant increases in collagen content, with more collagen in FS188 than in FS120 tumours. Conclusion: Results support the notion that MSCs play an important role in radiation-induced CAF activity and fibrosis in sarcoma. MCP-1 was identified as an important mediator of these effects. Moreover, endothelial cells were shown to play an important role in the recruitment of MSCs in response to radiation. In vitro results identifying FS188 cells as being more pro-fibrotic than FS120 cells were consistent with in vivo results. Further work to understand these processes should help to develop novel treatment strategies for combination with radiotherapy

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis

Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

The Transforming Growth Factor-beta (TGF-β) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-β signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-β, which is responsible for activation -transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies