Hot Off the Press: Collagen and Carcinomas

Collagen is the most abundant protein in the human body. Without it, our connective tissues—bone, skin, and tendons—would lose their most crucial properties leading to devastating disorders. Several of the collagen-related diseases stem from the inability to join different collagen chains into proper combinations. For example, some rare cases of connective tissue disorders with joint hypermobility and cardiac valvular problems are caused by mutations in COL1A2, the gene coding for the type I collagen α2(I) chain. The absence of the α2 chain triggers the irregular formation of type I collagen containing only the α1 chain, known as α1 homotrimers.

While studying the α1-homotrimers found in patients with collagen α2(I)-deficiency, a group led by Dr. Elena Makareeva in the lab of Dr. Sergey Leikin at NICHD discovered homotrimer resistance to enzymes that normally cleave collagen, known as MMPs. Makareeva's keen insight into the function of MMPs led her to question if collagen homotrimers, which can be found in cancerous tissue, are responsible for cancer cell invasion.

To verify that α1-homotrimers were indeed immune to MMP activity, Makareeva's team mixed human and mouse collagens, both in heterotrimeric and homotrimeric forms, with four different types of human MMPs. In all cases, the collagen homotrimers were cleaved five to ten times slower than the heterotrimers, with no difference between human and mouse collagens.

Makareeva next asked if the collagen homotrimers reported in cancer cells were synthesized in the cancer cells themselves. To this end, she grew normal fibroblasts, a cell type known to synthesize collagen, and nine different cancer cell lines in culture. While the normal fibroblasts contained only collagen heterotrimers, 15% to 40% of the collagen in cancer cells was homotrimeric. Makareeva's team found similar results after injecting human cancer cells into a mouse recipient, confirming that cancer tissue—not normal tissue—produces collagen homotrimers.

Why might cancer cells produce collagen homotrimers? In a final experiment, Makareeva's team found that cancer cells divide and migrate faster on a cell culture substrate containing homotrimer rather than heterotrimer fibers. “We propose that cancer cells may use MMP-resistant homotrimer fibers as invasion roadways,” explains Makareeva.

In the future, Makareeva hopes to find specific probes that will home in on collagen homotrimers, while avoiding collagen heterotrimers. She states that researchers could use probes for tumor detection and treatment. “Such a probe may work as a delivery tool, bringing drugs only to tumor cells,” explains Makareeva, “or it may help to visualize the leading edge of a tumor, which is crucial during surgery.”

Reference: Makareeva et al. Carcinomas Contain a Matrix Metalloproteinase-Resistant Isoform of Type I Collagen Exerting Selective Support to Invasion. Cancer Research: 70(11) June 1, 2010.