## 5 Extracellular Components of the CRC Microenvironment  
### Extracellular Matrix (ECM)  
The extracellular matrix is an integral component of the tumor microenvironment, serving structural functions as a scaffold for tissue cells and acting as a rich source of proteins and sugars involved in cellular processes [230, 231]. The ECM is a dynamic structure that remodels itself as needed, such as during tissue development [232]. The main components of the ECM include basement membranes, fibers (such as fibronectin, laminin, collagen, tenascin, and elastin), and soluble components (heparin, cytokines, growth factors, and mediators). However, the composition of the ECM varies depending on the location and is specific to each tissue [233, 234, 235]. 1.1 Degradation of the Extracellular Matrix in the CRC Microenvironment and Its Impact on Cancer Progression  
In the tumor microenvironment, the ECM undergoes structural changes due to strong exposure to the actions of cancer cells and niche conditions (hypoxia, reduced pH, free radicals, and stromal cells), contributing to cancer progression by facilitating the proliferation of cancer cells, local invasion, and migration to distant sites [234, 236]. First, the physical barrier that limits proliferating cells is broken. Second, bioactivity are released into the extracellular environment, and many binding sites for cell receptors are exposed [218]. There are two pathways of tumor invasion involving ECM remodeling. One is the degradation of the ECM, mediated by MMPs, which are proteins with proteolytic activity. They influence the loss of cell adhesion by mediating the dissociation of intercellular and cell-ECM connections, resulting in the loosening of the primary tumor structure and release from the primary niche. MMPs include collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP-2 and MMP-9), matrilysins (MMP-26 and MMP-7), stromelysins (MMP-3 and MMP-10), membrane-type (MT-MMP), and unclassified MMPs. Cancer cells are not the main producers of metalloproteinases but release interleukins, growth factors, or extracellular matrix metalloproteinase inducer (EMMPRIN), which stimulate other stromal cells to MMP production [218, 237]. Studies conducted on samples taken from CRC patients have shown increased levels of MMPs. The impact of the CRC niche on MMP production was examined using M2 macrophages, and it was found that CRC cells isolated from a late-stage tumor (SW480 cell line) showed increased gene expression encoding MMP-9 when treated with medium derived from M2 macrophages [238]. MMP-7 has been classified as a prognostic marker in CRC [239], and MMP-25 (MT6-MMP) has shown increased expression, correlating with the invasive phenotype of CRC [240]. However, the action of MMPs depends on activators, such as tissue plasminogen activator (tPA) and \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Cellular Elements of the CRC TME** & **Pro-Tumor Effect** & **Factors** & **References** \\ \hline \multirow{4}{*}{TAMs} & Proliferation & TGF-\(\beta\)1, NADPH Oxidase, ROS, VEGFR & [98] \\  & Immunosupression & Arg-1, iNOS, IL-10, PD-1, CCL-2, & [96, 98] \\  & Invasion and migration & CCL-3, CCL-4, CCL-5, CCL-20 & [98, 226] \\  & Angiogenesis & MMP-9, MMP-2, IL-6, TGF- \(\beta\), CCL-20 & [98, 226] \\  & Angiogenesis & VEGF, VEGF, EGF, FGF-2, IL-8, IL-1, IL-6, TNF-\(\alpha\), & [96, 98, 226, 227] \\  & CXCL-12, MMP-9, MMP-2 & & \\ \hline \multirow{4}{*}{CAFs} & Proliferation & EGF, PDGF, HGF, bFGF, IL-11, IL-6 & [140, 147, 163] \\  & Immunosupression & PGE2 & [228] \\ \cline{1-1}  & Invasion and migration & MMP-2, CCL-5, CCL-2, PDGF, HGF, IGFBP, IL-6 & [140, 166, 228, 229] \\ \cline{1-1}  & Angiogenesis & VEGF, IL-6 & [140, 228] \\ \hline \multirow{2}{*}{MDSCs} & Immunosupression & high ROS, ONOO\(-\), iNOS, & [204] \\ \cline{1-1}  & & Arg-1 & \\ \hline Vascular cells & Angiogenesis & VEGF & [216] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Cellular elements of the CRC microenvironment and the pro-tumor factors they produce.