Thy-1+ Cancer-associated Fibroblasts Adversely Impact Lung Cancer Prognosis

Abstract

Cancer-associated fibroblasts (CAFs) regulate diverse intratumoral biological programs and can promote or inhibit tumorigenesis, but those CAF populations that negatively impact the clinical outcome of lung cancer patients have not been fully elucidated. Because Thy-1 (CD90) marks CAFs that promote tumor cell invasion in a murine model of KrasG12D–driven lung adenocarcinoma (KrasLA1), here we postulated that human lung adenocarcinomas containing Thy-1+ CAFs have a worse prognosis. We first examined the location of Thy-1+ CAFs within human lung adenocarcinomas. Cells that co-express Thy-1 and α-smooth muscle actin (αSMA), a CAF marker, were located on the tumor periphery surrounding collectively invading tumor cells and in perivascular regions. To interrogate a human lung cancer database for the presence of Thy-1+ CAFs, we isolated Thy-1+ CAFs and normal lung fibroblasts (LFs) from the lungs of KrasLA1 mice and wild-type littermates, respectively, and performed global proteomic analysis on the murine CAFs and LFs, which identified 425 proteins that were differentially expressed. Used as a probe to identify Thy-1+ CAF-enriched tumors in a compendium of 1,586 lung adenocarcinomas, the presence of the 425-gene signature predicted a significantly shorter survival. Thus, Thy-1 marks a CAF population that adversely impacts clinical outcome in human lung cancer.

CD90 expression in human intrahepatic cholangiocarcinoma is associated with lymph node metastasis and poor prognosis

“…In some ICC specimens, CD90 + cells were present in the tumor stroma. There have been a number of reports concerning the relationship between stromal CD90 expression and prognosis, and the significance of cancer‐associated fibroblasts (CAFs) in the ICC stroma . Therefore, we examined CD90 and α‐SMA expression by double immunofluorescence staining to explore the possibility that the CD90 + cells observed were CAFs.…”

Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma

“…Although CAFs are one of the major stromal cell types in the HCC microenvironment [20, 21], the exact location of CAFs in HCC tissues, which reflects and may directly determine the heterogeneous cellular origin and functions of CAFs, has not been fully characterized and has not attracted sufficient attention. The location of CAFs in the TME is often detected by immunohistochemistry, which includes several different visualization methods, such as enzyme-linked immunohistochemical staining and immunofluorescence (IF) histochemical staining, and involves probing for detection of common protein markers in CAFs, such as α-SMA and FAP [22]. Until now, most studies determining the distribution of CAFs in HCC tissues by immunohistochemistry have simply indicated their distribution in the tumor fibrous stroma without determining their precise location, instead focusing on the numbers of CAFs and their relationships with HCC clinicopathological features and prognosis [23–25].…”

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…Multiple transcriptional programs have been identified that distinguish cancer-associated fibroblasts from healthy lung fibroblasts in NSCLC (40,174,178). These transcriptional signatures are associated with poor prognosis in NSCLC and center on genes that modulate cell-ECM interactions (40,174,178). In addition, increased matrix stiffness due to higher levels of collagen crosslinking within the tumor activates stromal α11β1-integrin signaling to promote the proliferation and increase the metastatic potential of NSCLC cancer cells (154).…”