Molecular biology of cancer-associated fibroblasts: can these cells be targeted in anti-cancer therapy?

Abstract

It is increasingly recognized that the non-neoplastic stromal compartment in most solid cancers plays an active role in tumor proliferation, invasion and metastasis. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types in the tumor stroma, and these cells are pro-tumorigenic. Evidence that CAFs are epigenetically and possibly also genetically distinct from normal fibroblasts is beginning to define these cells as potential targets of anti-cancer therapy. Here, we review the cell-of-origin and molecular biology of CAFs, arguing that such knowledge provides a rational basis for designing therapeutic strategies to coordinately and synergistically target both the stromal and malignant epithelial component of human cancers.

Fig. 1. Anti–5-methyl-C immunohistochemistry showing loss of CpG methylation in myofibroblasts in a mouse model of gastric carcinoma

These transgenic hypergastrinemic mice (INS GAS) on an FVB background develop gastric carcinoma in situ after infection with Helicobacter felis. Top (A,C) and bottom (B,D), wild type (FVB) and INS GAS + H. felis infected stomach sections stained for anti-αSMA and anti-5-methylcytosine (anti-5meC) in serial sections. The αSMA-positive spindle-shaped myofibroblasts of the normal muscularis mucosae, as well as the few αSMA-positive intraepithelial myofibroblasts, showed uniformly strong staining in multiple sections examined. In contrast, in a lesion with carcinoma-in-situ, the anti-5-methylcytosine staining of the more abundant αSMA-positive cells is significantly reduced (arrows).

Fig. 2. Anti-DNMT1 immunohistochemistry in human intestinal type gastric cancer

A. 10×; B. 40×. Almost all DNMT1 positive cells are seen in the tumor epithelium and not in the stroma. Thus while DNMT1 mRNA expression can be detected in the stromal cells by sensitive RT-PCR, the protein levels appear much reduced relative to the levels in the malignant epithelial cells. On serial sections the stromal cells were strongly αSMA positive (not shown).

Fig. 3. Changes in global methylation in malignant epithelium and CAFs

Two populations of cells (epithelial, blue; stromal, green) are shown at three stage of neoplastic progression. The nuclear color corresponds to the global methylation index. Based on our findings in gastric cancers, hypomethylation, as indicated by decreased nuclear staining, is seen early in CAFs and occurs somewhat later in the malignant epithelial cells. Hypomethylation is seen in both compartments at the carcinoma in situ/invasive cancer stage. How this scenario may generalize to other types of epithelial cancers is under investigation.