Cancer’s ability to ‘hijack’ regulatory mechanism increases metastasis

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scaffolding concept_oncology news australiaWhen skyscrapers go up, contractors rely on an infrastructure of steel beams and braces. Some cancers grow the same way, using a biological matrix from which the tumour can thrive and spread.

Scientists at The University of Texas MD Anderson Cancer Center and The University of North Carolina at Chapel Hill (UNC) have found that one component of this human scaffolding called collagen “cross-links” can determine a tumour’s ability to grow and spread. These cross-links of protein complexes enable connective tissue cells known as “stroma” to stiffen, stimulating tumour cell invasion and metastasis.

 

Collagen is the most common type of scaffolding protein, contributing to tissue strength. Various aspects of collagen metabolism do not function normally in cancers originating in epithelial tissues and have been an area of intense study.

The MD Anderson/UNC team studied two collagen cross-links, HLCC (hydroxylysine aldehyde-derived collagen cross-links) and LCC (lysine aldehyde-derived collagen cross-links) in mice and human epithelial lung cancer specimens. UNC team member Mitsuo Yamauchi, Ph.D., found that HLCCs are most commonly found in skeletal tissues, while LCCs are normally seen in soft tissues.

“We observed that tumour stroma had higher amounts of HLCC and lower amounts of LCC than what is found in normal tissue,” said Jonathan Kurie, M.D., professor, Department of Thoracic/Head and Neck Medical Oncology. “Expression of the gene LH2 or lysyl hydroxylase 2 in tumour cells increased the HLCC-to-LCC ratio in tumour stroma and enhanced tumour stiffness leading to metastasis. These findings suggest that the types of collagen cross-links in cancer may play a crucial role in regulating stromal stiffness and determining tumour cell metastatic fate.”

Because LH2 enhances tumour cells’ ability to metastasise, it functions as a regulatory “switch.” Thus, LH2 is able to control the relative abundance of biochemically distinct types of collagen cross-links in the tumour stroma, said Kurie. This finding has therapeutic potential because the enzymatic activity of LH2 might be inhibited selectively with small molecules that bind to LH2.

“Our investigation presented the first evidence that the types of collagen cross-links in tumour stroma are important in determining stromal stiffness and tumour cell metastatic potential,” said Kurie.

Source: University of Texas M. D. Anderson Cancer Center

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