The study uncovers a link between tissue tension and tumor formation, suggesting that the stiffness of a tissue can influence molecular signals that promote the malignant behavior of tumor cells. The findings, published in the September issue of Cancer Cell, provide exciting new insight into the mechanisms that link the tissue microenvironment with tumorigenesis, and may identify new targets for tumor therapies.
Tumors are more rigid than normal tissues, and palpation of compliant tissues to look for a rigid tissue mass has been used as a method of cancer detection for some time. However, the relationship between tissue stiffness and the behavior of tumor cells is not well understood. Dr. Valerie M. Weaver, from the University of Pennsylvania in Philadelphia, and colleagues examined cancer cells developing within a three-dimensional gel system in which rigidity could be carefully controlled to look at how tissue stiffening might drive malignant behavior of cancer cells.
Research focused on a class of molecules called integrins that function as transducers of physical cues and are known to regulate growth factor signaling. The researchers found that even a slight increase in the stiffness of the surrounding matrix perturbed tissue architecture and enhanced growth by inducing Rho-generated cytoskeletal tension to promote assembly of integrin-associated attachments called focal adhesions and increase growth factor-dependent ERK activation. Further, a decrease in Rho or ERK activity in cancerous cells was associated with a subsequent decline of focal adhesions and a reversion of aberrant morphological structures.
The results of the research study provide a link between exogenous force, Rho-associated cytoskeletal tension, focal adhesions, and growth factor activation of ERK, and offer a fresh perspective for understanding the molecular basis of tissue differentiation and tumor formation. According to Dr. Weaver, "ERK and Rho appear to be part of an integrated mechanoregulatory circuit that functions to link physical cues through integrins to molecular pathways that control cell growth. A chronic increase in cytoskeletal tension could enhance growth and perturb tissue organization, thereby promoting malignant transformation of a tissue."
The researchers include Matthew J. Paszek, Nastaran Zahir, Kandice R. Johnson, Johnathon N. Lakins, Gabriela I. Rozenberg, Cynthia A. Reinhart-King, Susan S. Margulies, David Boettiger, Daniel A. Hammer, and Valerie M. Weaver of the University of Pennsylvania in Philadelphia, Pennsylvania; Amit Gefen of Tel Aviv University in Tel Aviv, Israel; and Micah Dembo of Boston University in Boston, Massachusetts. This work was supported by NIH grant CA078731 and DOD grants DAMD1701-1- 0368, 1703-1-0496, and W81XWH-05-1-330 to V.M.W.; NIH grants HL57204 (to S.S.M.), GM57388 (to D.B.), BRP HL6438801A1 (to V.M.W. and D.A.H.), and T32HL00795404 (to N.Z. and K.R.J.); and DOD grants DAMD17-01-1-0367 and 17-03-1-0421 to J.N.L. and G.I.R.
Paszek et al.: "Tensional homeostasis and the malignant phenotype" Publishing in Cancer Cell, Vol. 8, September 2005, pages 241-254. DOI 10.1016/j.ccr.2005.08.010 www.cancercell.org
Journal
Cancer Cell