Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jul-Sep;3(3):288-92.
doi: 10.4161/cam.3.3.8888. Epub 2009 Jul 27.

Regulation of cancer invasiveness by the physical extracellular matrix environment

Aron Parekh  1 , Alissa M Weaver
Affiliations

Regulation of cancer invasiveness by the physical extracellular matrix environment

Aron Parekh et al. Cell Adh Migr. 2009 Jul-Sep.

Abstract

Long-term clinical outcomes are dependent on whether carcinoma cells leave the primary tumor site and invade through adjacent tissue. Recent evidence links tissue rigidity to alterations in cancer cell phenotype and tumor progression. We found that rigid extracellular matrix (ECM) substrates promote invasiveness of tumor cells via increased activity of invadopodia, subcellular protrusions with associated ECM-degrading proteinases. Although the subcellular mechanism by which substrate rigidity promotes invadopodia function remains to be determined, force sensing does appear to occur through myosin-based contractility and the mechanosensing proteins FAK and p130(Cas). In addition to rigidity, a number of ECM characteristics may regulate the ability of cells to invade through tissues, including matrix density and crosslinking. 3-D biological hydrogels based on type I collagen and reconstituted basement membrane are commonly used to study invasive behavior; however, these models lack some of the tissue-specific properties found in vivo. Thus, new in vitro organotypic and synthetic polymer ECM substrate models will be useful to either mimic the properties of specific ECM microenvironments encountered by invading cancer cells or to manipulate ECM substrate properties and independently test the role of rigidity, integrin ligands, pore size and proteolytic activity in cancer invasion of various tissues.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Potential rigidity sensing mechanisms by invadopodia. (A) Invadopodia are typically identified by colocalization of fluorescent antibodies for actin and cortactin at puncta that correspond to areas of ECM degradation visualized as dark regions in FITC-labeled fibronectin (Fn) overlaying gelatin. In this case, ECM was layered on top of either soft (storage modulus = 360 Pa) or hard (storage modulus = 3,300 Pa) polyacrylamide gels (PA) to determine if invadopodia activity was regulated by differences in mechanical properties. On hard PA, invasive MCF10ACA1d breast carcinoma cells produced more invadopodia and degraded more ECM than on soft PA. Yellow arrows indicate examples of invadopodia. (B) The localization of rings of the contractile protein myosin IIA (myoIIA) surrounding invadopodia (actin puncta) suggests a role for these structures in mechanosensing by potentially linking invadopodia with the contractile apparatus to detect differences in substrate rigidity. An example ring structure is indicated with a yellow arrow and shown in the zoomed portion of the myosin IIA image, and an example of no or weak localization of myosin IIA with an invadopodium is indicated with the red arrow. (C) Activated forms of FAK and p130Cas localize to invadopodia and depend on cytoskeletal contractility. Rings of myosin IIA also frequently surround invadopodia. These results suggest that invadopodia may act as mechanosensing organelles, either directly through localized mechanoresponsiveness at the invadopodia or through longer-range connections to neighboring or even distant focal adhesions. In either case, traction forces may be generated as a result of changes in cytoskeletal tension in response to ECM properties. Alternatively, invadopodia function could be regulated in the absence of local traction forces, secondary to distant intracellular signaling that leads to alterations in whole cell phenotypic changes. (A and B) are reprinted from Current Biology, Volume 18, Nelson R. Alexander, Kevin M. Branch, Aron Parekh, Emily S. Clark, Izuchukwu C. Iwueke, Scott A. Guelcher and Alissa M. Weaver, Extracellular Matrix Rigidity Promotes Invadopodia Activity, pp. 1295–9, 2008; with permission from Elsevier.
Figure 2
Figure 2
Navigation of basement membranes and stromal collagen by invading cancer cells. Invasive cancer cells are thought to navigate different tissue microenvironments in the process of invasion. In order for invasion to occur, tumor cells must first breach the basement membrane, a thin and highly crosslinked specialized ECM that requires proteolytic degradation for subsequent transmigration. Once past this barrier, cells must proceed through the neighboring stroma composed of collagenous connective tissue. The meshwork in the stroma is looser and may facilitate diverse migration modes dependent on local microenvironmental conditions and cellular cohesiveness. These modes of migration include a single cell, proteinase-independent amoeboidal phenotype (left) and single cell (middle) and collective (right) proteinase-dependent mesenchymal phenotypes that locally degrade matrix at enzymatically active invadopodia. Note the absence of collagen stroma surrounding and along the migration track of proteolytically active cells. New physiologically relevant models that mimic these interactions in vitro will be useful to elucidate mechanisms of cancer cell migration and invasion in various tissues.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Engler AJ, Griffin MA, Sen S, Bonnemann CG, Sweeney HL, Discher DE. Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J Cell Biol. 2004;166:877–887. - PMC - PubMed
    1. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–689. - PubMed
    1. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241–254. - PubMed
    1. Pelham RJ, Jr, Wang Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci USA. 1997;94:13661–13665. - PMC - PubMed
    1. Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ. ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol. 2003;163:583–595. - PMC - PubMed

Publication types

LinkOut - more resources