The Role of Type IV Collagen and Basement Membranes in Cancer Progression and Metastasis

Abstract

The basement membrane acts as a barrier separating the epithelium from the surrounding stroma. While the structural role of the basement membrane in defining tissue architecture and compartmentalization has been appreciated for decades, its dynamic role in the regulation of cell behavior and recruitment of signaling pathways is only now emerging.1 The basement membrane further defines the tumor microenvironment and provides significant host-derived regulatory signals during progression of tumor growth and metastasis. The major component of the basement membrane is known to be type IV collagen.1 Nevertheless, a precise role for type IV collagen in its assembled suprastructural form versus its unassembled/degraded form is primarily unknown. In this issue of The American Journal of Pathology, Ikeda and colleagues2 demonstrate the effect of promoter hypermethylation on the expression levels of COL4A5/COL4A6 collagen genes. They suggest that such hypermethylation leads to diminished levels of α5(IV) and α6(IV) collagen in colorectal cancer tissue and colon cancer cells. The normal production and assembly of the basement membrane is disrupted in this malignant process. This data is consistent with evidence emerging from recent studies examining different cancer tissues, including prostate cancer, using antibodies generated in the Sado Ninomiya laboratory.3–8 However, a lack of free access to these antibodies to all investigators has limited independent evaluation. In vitro studies demonstrate that the expression of α5(IV) and α6(IV) collagen is down-regulated in association with hypermethylation of the bidirectional promoter of COL4A5/COL4A6 genes in colon cancer cell lines.2 These results suggest that normal assembly and organization of the basement membrane is disrupted in cancer progression.2 In an earlier study, Tanaka and colleagues9 analyzed the expression of the α1(IV) to α6(IV) collagen chain assembly by immunohistochemical analysis in colorectal cancer tissue, revealing normal expression of α1(IV)/α2(IV) and α5(IV)/α6(IV) chains but lost expression of α5(IV)/α6(IV) chains upon cancer invasion. These authors suggested that loss of α5(IV)/α6(IV) expression in the invasive cancer may be attributable to remodeling of basement membrane assembly, which in turn may be regulated by gene expression. The present article by Ikeda and colleagues2 now further demonstrates that such loss may be at the gene expression level.