Cancer-associated fibroblasts – Not-so-innocent bystanders in metastasis to bone? (original) (raw)

Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Pr...

Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy

Expert Opinion on Therapeutic Targets, 2005

Stroma cells contribute to the microenvironment that is essential for cancer growth, invasion and metastatic progression. Fibroblasts, often termed myofibroblasts or cancer-associated fibroblasts (CAFs), represent the most abundant cell type in the tumour stroma. The demonstrated tumour-promoting capacities of CAFs has increased the interest to exploit them as drug targets for anticancer therapy. Although single factors, such as platelet-derived growth factor, transforming growth factor-β1, hepatocyte growth factor and matrix metalloproteinases have been identified as mediators in the fibroblast tumour interaction, the morphological and functional differences of CAFs compared with their normal counterparts are only incompletely understood. Recently, novel global methods for gene expression profiling were applied to comprehensively characterise CAFs from breast, pancreas, colon and basal cell cancer in their in situ environment. The analysis of different CAF preparations revealed regulated genes that were previously not described in the tumourstroma context. Additionally, besides a few striking overlaps, the comparison of the gene lists indicates a high level of heterogeneity in the expression pattern of CAFs from different tumour types. Together, these studies emphasise the importance of cross-talk between stromal and malignant cells of the tumour. It is likely that the continued characterisation of this interaction, and the molecular identification of key mediators, will provide insights into tumour biology and suggest novel therapeutic options.

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Cancers

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the fail...

Fibroblasts in the Tumor Microenvironment: Shield or Spear?

International Journal of Molecular Sciences, 2018

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.

Cancer-associated fibroblasts and tumor growth – bystanders turning into key players

Current Opinion in Genetics & Development, 2009

Novel mechanisms, and molecular mediators, of the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified. These include CXCL12/SDF-1-mediated recruitment of bone marrow-derived endothelial precursor cell and pro-metastatic effects of CCL5. Co-culture experiments also suggest that CAFs can influence the drug-sensitivity of cancer cells. Comparisons of CAFs from different tumors have started to identify tumor-type specific differences in CAF gene expression and marker protein profiling indicates the existence of multiple distinct co-existing CAF-subsets. Studies in animal models have demonstrated that CAFs can be derived from bone marrow-derived cells or from epithelial or endothelial cells undergoing mesenchymal transition. The genetic status of CAFs remains controversial following conflicting findings. Meanwhile, analyses of CAFs from human tumors have revealed consistent epigenetic changes. An increasing number of translational studies have emphasized the prognostic significance of different CAF-related tumor characteristics. Clinical studies aiming at CAF-targeting can now be envisioned based on findings from experimental intervention studies with agents targeting, for example FAP or PDGF-, TGF-beta- or hedgehog-signaling.

Role of cancer-associated fibroblasts in tumor microenvironment

Elsevier eBooks, 2022

Ovarian cancer (OVAC) remains the most lethal gynecological malignancy; it is ranked fifth among the most common types of cancer that affect women worldwide. Several aspects of the disease, including molecular pathogenesis, epidemiology, histological subtypes, poor prognosis at early stages due to the absence of specific signs and symptoms, and curative treatments in the advanced stages are all responsible for the poor survival rate, which is evaluated to be at 5 years once the cancer is diagnosed and treatment begins. A better understanding of the pathogenesis of ovarian cancer is therefore crucial, even though unexplored pathways, in order to improve the prognosis of patients with OVAC and to develop novel therapeutic approaches. Accordingly, the tumor microenvironment, defined as the combination of proteins produced by all tumor cells and by non-cancerous cells or the stroma, and composed of several cells, including those from the immune, inflammatory and adipose systems, as well as the mesenchymal stem, endothelial and fibroblasts cells, has recently attracted attention. Of particular interest are fibroblasts, which can be activated into cancer-associated fibroblast (CAFs) to become a potent supporter of carcinogenesis, promoting the initiation of epithelial tumor formation, tumor growth, angiogenesis and metastasis, as well as therapeutic resistance and immunosuppression. Thus, the targeting of CAFs for early diagnosis and effective therapy warrants our attention. In this review, we discuss the mechanisms through which CAFs may affect the structure, composition and microenvironment of the ovarian tumor. We also aim to highlight important aspects of OVAC pathobiology involving CAFs, in an attempt to provide insight into novel diagnostic windows and provide new therapeutic perspectives. Contents 1. Introduction 2. Role of ovarian fibroblasts 3. Origin of ovarian CAFs 4. Mechanisms through which CAFs affect tumor structure, composition and the microenvironment in ovarian cancer 5. Targeting CAFs for diagnosis and cancer therapy 6. Conclusions and perspectives

Carcinoma-associated fibroblasts provide operational flexibility in metastasis

Seminars in Cancer Biology, 2014

Malignant cancer cells do not act as lone wolves to achieve metastasis, as they exist within a complex ecosystem consisting of an extracellular matrix scaffold populated by carcinomaassociated fibroblasts (CAFs), endothelial cells and immune cells. We recognize local (primary tumor) and distant ecosystems (metastasis). CAFs, also termed myofibroblasts, may have other functions in the primary tumor versus the metastasis. Cellular origin and tumor heterogeneity lead to the expression of specific markers. The molecular characteristics of a CAF remain in evolution since CAFs show operational flexibility. CAFs respond dynamically to a cancer cell's fluctuating demands by shifting profitable signals necessary in metastasis. Local, tissue-resident fibroblasts and mesenchymal stem cells (MSCs) coming from reservoir sites such as bone marrow and adipose tissue are the main progenitor cells of CAFs. CAFs may induce awakening from metastatic dormancy, a major cause of cancer-specific death. Cancer management protocols influence CAF precursor recruitment and CAF activation. Since CAF signatures represent early changes in metastasis, including formation of pre-metastatic niches, we discuss whether liquid biopsies, including exosomes, may detect and monitor CAF reactions allowing optimized prognosis of cancer patients.

A framework for advancing our understanding of cancer-associated fibroblasts

Nature Reviews Cancer, 2020

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, whic...