�New enquiry may explain why breast cancer tends to be more aggressive in women with denser breast tissue.
Breast cancer cells grown in dense, stiff surroundings footprint up their invasive activities, Vanderbilt-Ingram Cancer Center investigators report in the Sept. 9 progeny of Current Biology.
The findings suggest a cellular mechanism for the correlation betwixt human breast tissue density and tumor aggressiveness. Women with increased breast concentration on mammograms have an increased risk for both developing breast cancer and having bosom cancers with invasive characteristics.
This connection between breast denseness and genus Cancer aggressiveness has begged the question of which comes first. Is the tissue paper denser because the tumor is more aggressive (and recruits cells that "lay down" more matrix), or is the tumor more aggressive because the tissue is denser?
"Our study shows that if you give birth a dense, rigid matrix, the cells will be more aggressive and invasive; it's a direct upshot," said Alissa Weaver, M.D., Ph.D., assistant professor of Cancer Biology and lead author of the study.
Weaver and colleagues were interested in invadopodia - the finger-like protrusions that a cancer cell uses to drill holes in the extracellular intercellular substance (matrix-degrading enzymes are associated with invadopodia). These structures are believed to be important for cancer invasion.
"If you have enough invadopodia, over time they'll make large holes that cells can move through to invade and metastasize," Weaver said.
Despite the intimate connection between invadopodia and the matrix, selfsame little was known about what theatrical role the matrix might play in regulation invadopodia subroutine. Weaver and colleagues started probing this question as part of computational math modeling project through the Vanderbilt Integrative Cancer Biology Center.
They were surprised to find that breast cancer cells cultured on a denser - and hence, more stiff - matrix had a greater number of active invadopodia than breast cancer cells civilized on a less thick matrix.
"We intellection that more 'stuff' for the cells to let through was going to make it harder, so we expected to envision less matrix degradation, only instead we found this interesting effect where cells actually sense the inflexibility and put down more," Weaver said.
The team examined how cells exchange a sense of matrix rigidity into intracellular signals, a treat called mechanotransduction.
Proteins that generate contractile forces, such as myosin "motors," are important players in mechanotransduction. Weaver and colleagues confirmed that myosin motors are involved in sparking more degradation by invadopodia in response to a rigid matrix, though the motors themselves are non present in the boring structures.
The investigators also concerned the activities of two signaling proteins called FAK and p130Cas in the rigidity-induced invadopodia activity. These signaling proteins were present in an activated state of matter in the invadopodia, suggesting that they are of import players in this reply and english hawthorn represent targets for anti-invasive therapies.
Weaver aforementioned that it's exciting to find a cellular mechanics that could explain why denser bosom tissue is correlated with more strong-growing tumors and a poorer prognosis for patients.
"The estimate that tissue paper rigidity leads to a more aggressive phenotype had been out there for a while," she aforesaid, "but it hadn't actually been tied to matrix degradation, which is thought to be important for metastasis and spread of cells through the body."
Because metastasis is often what makes cancers deadly, new leads on how to block it are vital, she added.
Nelson Alexander, Ph.D., Kevin Branch, Aron Parekh, Ph.D., Emily Clark, Ph.D., and Izuchukwu Iwueke, in the Department of Cancer Biology at Vanderbilt, and Scott Guelcher, Ph.D., in the Department of Chemical Engineering at Vanderbilt, contributed to the studies. The National Institutes of Health and the Vanderbilt University School of Engineering supported the research.
Source: Dagny Stuart McMillin
Vanderbilt University Medical Center
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