Podoplanin, α-Smooth Muscle Actin or S100A4 Expressing Cancer-Associated Fibroblasts Are Associated with Different Prognosis in Colorectal Cancers

Abstract

The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), α-smooth muscle actin (α-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or α-SMA CAFs were detected in all the cases. PDPN/S100A4 and α-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN+ CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN-/α-SMAhigh CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN-/S100A4high CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN+ CAF phenotype is distinct from the α-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN-/α-SMAhigh or PDPN-/S100A4high CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.

Isolation of cancer‐associated fibroblasts and its promotion to the progression of intrahepatic cholangiocarcinoma

“…It has been demonstrated that α‐SMA is widely expressed in CAFs and associated with poor prognosis of patients in various types of cancers, including oral tongue squamous cell carcinoma, hepatocellular carcinoma, non‐small‐cell lung cancer, and colorectal carcinoma . In our study, it was found that majority of ICC (86/106) are characterized by α‐SMA expression in CAFs.…”

“…It has been demonstrated that α-SMA is widely expressed in CAFs and associated with poor prognosis of patients in various types of cancers, including oral tongue squamous cell carcinoma, hepatocellular carcinoma, nonsmall-cell lung cancer, and colorectal carcinoma. [35][36][37][38] In our study, it was found that majority of ICC (86/106) are F I G U R E 3 CAFs promote proliferation, migration, and invasion of cholangiocarcinoma cells in vitro. A, The growth of cholangiocarcinoma cells (HuCCT-1 and RBE) cultured with CAFs-conditioned medium (CAFs-CM) was greatly accelerated compared with cells cultured with normal fibroblasts-conditioned medium (NFs-CM) and 10% FBS medium, especially on day 3 (P < 0.001), day 4 (P < 0.0001), and day 5 (P < 0.0001).…”

Suppression of MAPK signaling in BRAF‐activated PTEN‐deficient melanoma by blocking β‐catenin signaling in cancer‐associated fibroblasts

“…c, there was a roughly 20% decrease in the percentage of PDGFR‐α‐positive (PDGFR‐α+) fibroblasts in Braf V600E ; Pten lox5/lox5 ‐bcat/Fb tumors. Next, we evaluated the expression of α‐smooth muscle actin (α‐SMA), which has been found to be a specific CAF marker within solid tumors (Augsten, ; Choi et al., ; Huet et al., ; Tsukamoto, Mishima, Hayashibe, & Sasase, ). α‐SMA expression was markedly reduced (60%) in Braf V600E ; Pten lox5/lox5 ‐bcatFb tumors (Fig.…”

“…Pten lox5/lox5 -bcat/Fb tumors. Next, we evaluated the expression of α-smooth muscle actin (α-SMA), which has been found to be a specific CAF marker within solid tumors (Augsten, 2014;Choi et al, 2013;Huet et al, 2008;Tsukamoto, Mishima, Hayashibe, & Sasase, 1992). α-SMA expression was markedly reduced (60%) in Braf V600E ;…”

Tumor-associated fibroblasts expression in esophageal squamous cell carcinoma and may descend from mesenchymal stem cells

“…They have an established biological impact on tumorigenesis as matrix synthesizing or matrix degrading cells and play a critical role in cancer aggressiveness and metastasis [8] [9]. α-SMA and S100A4 expressions are recognized not only in the TAFs but also in smooth muscle cells, thus suggesting limitations for interpretation of their stromal positivity [10] [11].…”