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Integrin α5β1 facilitates cancer cell invasion through enhanced contractile forces.

ABSTRACT: Cell migration through connective tissue, or cell invasion, is a fundamental biomechanical process during metastasis formation. Cell invasion usually requires cell adhesion to the extracellular matrix through integrins. In some tumors, increased integrin expression is associated with increased malignancy and metastasis formation. Here, we have studied the invasion of cancer cells with different α5β1 integrin expression levels into loose and dense 3D collagen fiber matrices. Using a cell sorter, we isolated from parental MDA-MB-231 breast cancer cells two subcell lines expressing either high or low amounts of α5β1 integrins (α5β1(high) or α5β1(low) cells, respectively). α5β1(high) cells showed threefold increased cell invasiveness compared to α5β1(low) cells. Similar results were obtained for 786-O kidney and T24 bladder carcinoma cells, and cells in which the α5 integrin subunit was knocked down using specific siRNA. Knockdown of the collagen receptor integrin subunit α2 also reduced invasiveness, but to a lesser degree than knockdown of integrin subunit α5. Fourier transform traction microscopy revealed that the α5β1(high) cells generated sevenfold greater contractile forces than α5β1(low) cells. Cell invasiveness was reduced after addition of the myosin light chain kinase inhibitor ML-7 in α5β1(high) cells, but not in α5β1(low) cells, suggesting that α5β1 integrins enhance cell invasion through enhanced transmission and generation of contractile forces.

SUBMITTER: Mierke CT

PROVIDER: S-EPMC3021998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The malignancy of a tumor depends on the capability of cancer cells to metastasize. The process of metastasis involves cell invasion through connective tissue and transmigration through endothelial monolayers. The expression of the glycosylphosphatidylinositol-anchored receptor CD24 is increased in several tumor types and is consistently associated with increased metastasis formation in patients. Furthermore, the localization of β1-integrins in lipid rafts depends on CD24. Cell invasion is a fundamental biomechanical process and usually requires cell adhesion to the extracellular matrix (ECM) mainly through β1 heterodimeric integrin receptors. Here, we studied the invasion of A125 human lung cancer cells with different CD24 expression levels in three-dimensional ECMs. We hypothesized that CD24 expression increases cancer cell invasion through increased contractile forces. To analyze this, A125 cells (CD24 negative) were stably transfected with CD24 and sorted for high and low CD24 expression. The invasiveness of the CD24(high) and CD24(low) transfectants was determined in three-dimensional ECMs. The percentage of invasive cells and their invasion depth was increased in CD24(high) cells compared with CD24(low) cells. Knockdown of CD24 and of the β1-integrin subunit in CD24(high) cells decreased their invasiveness, indicating that the increased invasiveness is CD24- and β1-integrin subunit-dependent. Fourier transform traction microscopy revealed that the CD24(high) cells generated 5-fold higher contractile forces compared with CD24(low) cells. To analyze whether contractile forces are essential for CD24-facilitated cell invasion, we performed invasion assays in the presence of myosin light chain kinase inhibitor ML-7 as well as Rho kinase inhibitor Y27632. Cell invasiveness was reduced after addition of ML-7 and Y27632 in CD24(high) cells but not in CD24(neg) cells. Moreover, after addition of lysophosphatidic acid or calyculin A, an increase in pre-stress in CD24(neg) cells was observed, which enhanced cellular invasiveness. In addition, inhibition of the Src kinase or STAT3 strongly reduced the invasiveness of CD24(high) cells, slightly reduced that of CD24(low) cells, and did not alter the invasiveness of CD24(neg) cells. Taken together, these results suggest that CD24 enhances cell invasion through increased generation or transmission of contractile forces.

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Integrin α5β1 facilitates cancer cell invasion through enhanced contractile forces.

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