Active SPARCL1 Slows Growth and Spread of Colorectal Cancer

The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. In order to study this important feature of tumorigenesis, investigators at the University of Erlangen-Nuremberg (Germany) isolated pure TECs (tumor endothelial cells) from human colorectal carcinomas (CRCs) that exhibited either improved or worse clinical prognosis.

Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. In particular, the gene encoding the matricellular protein SPARCL1 was most strongly upregulated in TECs from tumors with improved prognosis. Matricellular proteins are dynamically expressed non-structural proteins that are present in the extracellular matrix (ECM). Rather than serving as stable structural elements in the ECM, these proteins are rapidly turned over and have regulatory roles. They characteristically contain binding sites for ECM structural proteins and cell surface receptors, and may sequester and modulate activities of specific growth factors.

The investigators reported in the October 10, 2016, online edition of the Journal of Clinical Investigation that when SPARCL1 expression was induced in vitro, it functionally contributed to quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown of this gene increased sprouting. In human colorectal cancer tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent endothelial cells inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels.

"Previously the assumption was that blood vessels always benefit tumor growth. However, we have shown that blood vessels, if they contain the protein SPARCL1, can also stem tumor growth," said senior author Dr. Michael Stürzl, professor of molecular and experimental surgery at the University of Erlangen-Nuremberg. "The study also shows why tumors in many cases continue to grow despite therapy intended to inhibit blood vessels. In tumors whose blood vessels produce SPARCL1 and which are already adequately supplied with oxygen and nutrients, suppression of the blood vessels could foster tumor growth. It is important to note that the study does not recommend that antiangiogenic therapy not be used, but rather explains why such therapies may not be effective in all patients."

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University of Erlangen-Nuremberg