The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.

Serum response factor (SRF) is a transcription factor known to mediate phenotypic plasticity in smooth muscle cells (SMCs). Despite the critical role of this protein in mediating intestinal injury response, little is known about the mechanism through which SRF alters SMC behavior. Here, we provide compelling evidence for the involvement of SRF-dependent microRNAs (miRNAs) in the regulation of SMC apoptosis. We generated SMC-restricted Srf inducible knockout (KO) mice and observed both severe degeneration of SMCs and a significant decrease in the expression of apoptosis-associated miRNAs. The absence of these miRNAs was associated with overexpression of apoptotic proteins, and we observed a high level of SMC death and myopathy in the intestinal muscle layers. These data provide a compelling new model that implicates SMC degeneration via anti-apoptotic miRNA deficiency caused by lack of SRF in gastrointestinal motility disorders.

Neurotransmitters are reported to be involved in tumor initiation and progression. This study aimed to elucidate the prognostic value of γ-aminobutyric acid type A receptor δ subunit (GABRD) in colon adenocarcinoma (COAD) using the data from The Cancer Genome Atlas (TCGA) database. The GABRD mRNA expression levels in the COAD and normal tissues were compared using the Wilcoxon rank-sum test. The correlation between clinicopathologic characteristics and GABRD expression was analyzed by Wilcoxon rank-sum test or Kruskal-Wallis test and logistic regression. The prognostic value of GABRD mRNA expression in patients with COAD was determined using the Kaplan-Meier curve and Cox regression analysis. Finally, the molecular mechanisms of GABRD in COAD were predicted by gene set enrichment analysis (GSEA). The COAD tissues exhibited higher GABRD mRNA expression levels than the normal tissues. The logistic regression analysis revealed that GABRD mRNA expression was correlated with TNM stage, N stage, M stage, and microsatellite instability (MSI) status. The Kaplan-Meier survival curve and log-rank test revealed that patients with COAD exhibiting high GABRD mRNA expression were associated with poor overall survival (OS). The multivariate analysis indicated that increased GABRD mRNA expression was an independent prognostic factor and was correlated with a poor OS. The GSEA revealed that GABRD was involved in signaling pathways, including cell adhesion molecules, gap junction, melanogenesis, and mTOR signaling pathway, as well as the signaling pathways associated with basal cell carcinoma or bladder cancer development. In summary, enhanced GABRD mRNA expression may be a potential independent prognostic biomarker for COAD.

Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca²⁺ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract.

Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-β (TGFβ) signaling. Platelet-derived growth factor receptor β (PDGFRβ), which is a receptor tyrosine kinase and is also a downstream signal of TGFβ, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRβ and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFβ treatment in the colon cancer cell line DLD-1. TGFβ and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRβ blockade. We propose that the PDGFRβ signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca²⁺-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRβ signaling due to increased TGFβ and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.