**4. Cancer-associated fibroblasts**

CAFs are heterogenous populations of cells within the tumour microenvironment that have different phenotypic characteristics even within the same type of cancer. The origin of the cells is diverse; usually arise from tissue-resident fibroblasts but can also be derived from adipocytes, endothelial cells, pericytes, stellate cells and bonemarrow derived mesenchymal stem cells [7]. The role of these CAFs in the tumour microenvironment is to shape the tumour microenvironment via tumour proliferation, neoangiogenesis, invasion, metabolic reprogramming, extracellular matrix remodelling, immunosuppression, and metastasis [6, 7].

These cells facilitate the crosstalk between cancer cells and the tumour microenvironment. In the tumour microenvironment, a crosstalk between cancer cells and stromal cells leads to the secretion of factors such as TGF-β, PGDF, connective tissue growth factor (CTGF), hepatocyte growth factor (HGF) and fibroblast growth factor 2 (FGF2), which initiates the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) [6, 7, 23, 29, 30]. Usually, their activation is via the NF-κB and JAK-STAT signalling pathways and is dependent on the secretion and release of signalling molecules such as TGF-β, stromal cell-derived factor-1 (CXCL12/SDF-1), platelet-derived growth factor α/β (PDGF α/β), basic fibroblast growth factor (b-FGF), RTK ligands, IL-1β and IL-6 by cancer or immune cells [6, 31]. The activation of CAFs is a common feature in tumorigenesis and these CAFs are perpetually activated unlike in normal tissues.

CAFs are a rich source of growth promoting molecules and proangiogenic factors as well as extracellular components such as growth factors, cytokines, and *Stromal Cells and Extracellular Vesicles DOI: http://dx.doi.org/10.5772/intechopen.106721*

extracellular matrix components. During cancer progression and metastasis, these cells secrete VEGF and TGF-β, which are crucial in angiogenesis and epithelial-mesenchymal transition (EMT) respectively [6, 7]. EMT is a vital step in metastasis via epigenetic changes, and it involves the loss of cell polarity and cell-to-cell adhesions by epithelial cells. In turn, these cells gain migratory and invasive phenotypes.

CAFs provide the physical scaffolding of cells and facilitate the migration of cancer cells through the tumour microenvironment by altering three-dimensional structure of ECM via the secretion of plasminogen activator protein and matrix metalloproteinase 3 (MMP3) that degrades E-cadherin to promote cancer cell invasion [9, 32, 33]. CAFs also migrate together with epithelial cancer cells thereby suggesting these cells play an important role in intravasation and extravasation of epithelial cells in metastasis by enhancing transmigration of cancer cells through endothelial cell layers [9, 32, 33]. In invasion of squamous cell carcinoma and breast cancer, CAFs create tracks through the ECM that cancer cells could not create on their own through Hippo-signalling dependent remodelling of ECM [9, 32, 33]. Activated fibroblasts also secrete elevated levels of ECM-degrading proteases such as matrix metalloproteases 2 and 9 (MMP2 and MMP9) [23]. Increase in ECM remodelling and degradation is associated with increase in metastasis.

Following activation by TGF-β, CAFs also modulate immune cells through factors such as monocyte chemoattractant protein-1 (MCP-1) and IL-1 leading to a pro-inflammatory microenvironment [23]. Activated CAFs also regulate collagen structure in the stroma of multiple solid tumours, including breast cancer. The cross-linking and alignment of collagen are associated with poor prognosis in cancer thus regulating invasion and metastasis [23]. CAFs also interact with the epithelium in breast cancer thus enhancing breast cancer progression and metastasis. In addition, CAFs also express programmed death ligand 1 (PD-L1) that leads to the suppression of CD8<sup>+</sup> T-cell immune responses and thence, progression of colon cancer [23].
