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Targeted therapies for colorectal cancer metastasis

Tue, 09/17/2019 - 15:17
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University of Kentucky Markey Cancer Center researchers focusing on Neuropilin-1 (NRP1), a transmembrane protein that has been connected to the progression of cancers and particularly metastasis, have identified two novel human NRP1 splice variants in colorectal cancer, both defective in N-linked glycosylation modification.

This defect leads to a constant amount of the NRP1 variants shuttling between the cell surface and the inside of the cell upon stimulation of HGF growth factor; it also leads to a decrease in the levels of NRP1 variants' degradation so as to their accumulation on endosomes, the membrane-bound compartments inside a cell.

The paper, ‘{{N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals}}, published in Nature Communications, provides new insight on targeted therapy for colorectal cancer metastasis.

These NRP1 variants form a complex with MET and β1-integrin receptors and transport together with these receptors into endosomes. This complex provides persistent endosomal signals to activate the FAK/p130Cas pathway, thereby promoting colorectal cancer cell migration, invasion and metastasis.

Additionally, the colorectal cancer cells that have formed NRP1 variants/MET/ β1-integrin complexes are resistant to drugs that inhibit MET tyrosine kinase activity, suggesting that colorectal cancer patients with these variants are likely to not respond to MET-targeted therapy.

"These variants may serve as a predictive marker for colorectal cancer metastasis," said study lead, Qing-Bai She, associate professor in the UK Department of Pharmacology and Nutritional Sciences. "Our findings provide a new avenue of exploration by blocking internalisation or formation of the NRP1 variants/Met/β1-integrin complexes or alternatively by inhibiting their endosomal signals on activation of FAK/p130Cas pathway for targeted therapies of colorectal cancer metastasis."

To access this paper, please click here