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• W2002203108 abstract "Metastasis is a key event of malignant tumor progression. The capability to metastasize depends on the ability of the cancer cell to migrate into connective tissue, adhere, and possibly transmigrate through the endothelium. Previously we reported that the endothelium does not generally act as barrier for cancer cells to migrate in three-dimensional extracellular matrices (3D-ECMs). Instead, the endothelium acts as an enhancer or a promoter for the invasiveness of certain cancer cells. How invasive cancer cells diminish the endothelial barrier function still remains elusive. Therefore, this study investigates whether invasive cancer cells can decrease the endothelial barrier function through alterations of endothelial biomechanical properties. To address this, MDA-MB-231 breast cancer cells were used that invade deeper and more numerous into 3D-ECMs when co-cultured with microvascular endothelial cells. Using magnetic tweezer measurements, MDA-MB-231 cells were found to alter the mechanical properties of endothelial cells by reducing endothelial cell stiffness. Using spontaneous bead diffusion, actin cytoskeletal remodeling dynamics were shown to be increased in endothelial cells co-cultured with MDA-MB-231 cells compared with mono-cultured endothelial cells. In addition, knockdown of the α5 integrin subunit in highly transmigrating α5β1high cells derived from breast, bladder, and kidney cancer cells abolished the endothelial invasion-enhancing effect comparable with the inhibition of myosin light chain kinase. These results indicate that the endothelial invasion-enhancing effect is α5β1 integrin-dependent. Moreover, inhibition of Rac-1, Rho kinase, MEK kinase, and PI3K reduced the endothelial invasion-enhancing effect, indicating that signaling via small GTPases may play a role in the endothelial facilitated increased invasiveness of cancer cells. In conclusion, decreased stiffness and increased cytoskeletal remodeling dynamics of endothelial cells may account for the breakdown of endothelial barrier function, suggesting that biomechanical alterations are sufficient to facilitate the transmigration and invasion of invasive cancer cells into 3D-ECMs. Metastasis is a key event of malignant tumor progression. The capability to metastasize depends on the ability of the cancer cell to migrate into connective tissue, adhere, and possibly transmigrate through the endothelium. Previously we reported that the endothelium does not generally act as barrier for cancer cells to migrate in three-dimensional extracellular matrices (3D-ECMs). Instead, the endothelium acts as an enhancer or a promoter for the invasiveness of certain cancer cells. How invasive cancer cells diminish the endothelial barrier function still remains elusive. Therefore, this study investigates whether invasive cancer cells can decrease the endothelial barrier function through alterations of endothelial biomechanical properties. To address this, MDA-MB-231 breast cancer cells were used that invade deeper and more numerous into 3D-ECMs when co-cultured with microvascular endothelial cells. Using magnetic tweezer measurements, MDA-MB-231 cells were found to alter the mechanical properties of endothelial cells by reducing endothelial cell stiffness. Using spontaneous bead diffusion, actin cytoskeletal remodeling dynamics were shown to be increased in endothelial cells co-cultured with MDA-MB-231 cells compared with mono-cultured endothelial cells. In addition, knockdown of the α5 integrin subunit in highly transmigrating α5β1high cells derived from breast, bladder, and kidney cancer cells abolished the endothelial invasion-enhancing effect comparable with the inhibition of myosin light chain kinase. These results indicate that the endothelial invasion-enhancing effect is α5β1 integrin-dependent. Moreover, inhibition of Rac-1, Rho kinase, MEK kinase, and PI3K reduced the endothelial invasion-enhancing effect, indicating that signaling via small GTPases may play a role in the endothelial facilitated increased invasiveness of cancer cells. In conclusion, decreased stiffness and increased cytoskeletal remodeling dynamics of endothelial cells may account for the breakdown of endothelial barrier function, suggesting that biomechanical alterations are sufficient to facilitate the transmigration and invasion of invasive cancer cells into 3D-ECMs. IntroductionThe malignancy of tumors is responsible for most cancer-related deaths. A benign tumor becomes malignant when cancer cells spread from the primary tumor and form metastases (1Frixen U.H. Behrens J. Sachs M. Eberle G. Voss B. Warda A. Löchner D. Birchmeier W. J. Cell Biol. 1991; 113: 173-185Crossref PubMed Scopus (1390) Google Scholar, 2Batlle E. Sancho E. Francí C. Domínguez D. Monfar M. Baulida J. García De Herreros A. Nat. Cell Biol. 2000; 2: 84-89Crossref PubMed Scopus (2149) Google Scholar, 3Cano A. Pérez-Moreno M.A. Rodrigo I. Locascio A. Blanco M.J. del Barrio M.G. Portillo F. Nieto M.A. Nat. Cell Biol. 2000; 2: 76-83Crossref PubMed Scopus (2871) Google Scholar, 4De Craene B. Gilbert B. Stove C. Bruyneel E. van Roy F. Berx G. Cancer Res. 2005; 65: 6237-6244Crossref PubMed Scopus (196) Google Scholar). The process of metastasis can be described in several steps that involve the dissemination of cancer cells from the primary tumor into the extracellular matrix (ECM), 2The abbreviations used are: ECMextracellular matrix3D-ECMthree-dimensional ECMHPMEChuman pulmonary microvascular endothelial cellHDMEChuman dermal microvascular endothelial cellHUVEChuman umbilical vein endothelial cellFNfibronectinPECAM-1platelet endothelial cell adhesion molecule-1VE-cadherinvascular endothelial-cadherinMSDmean square displacementCFDAcarboxyfluorescein diacetateMFImean fluorescence intensityMCmono-culturedCCco-cultured. the invasion of cancer cells through connective tissue, adhesion of cancer cells to the endothelium of blood or lymph vessels, possibly the transmigration of cancer cells through the endothelium (intravasation and/or extravasation), and subsequently, the formation of a secondary tumor in a distant targeted organ (5Steeg P.S. Nat. Med. 2006; 12: 895-904Crossref PubMed Scopus (1629) Google Scholar, 6Al-Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (565) Google Scholar).The impact of endothelial cells on the regulation of cancer cell invasiveness into 3D-ECMs is so far unknown. The regulation of cancer cell invasiveness may be a complex scenario that is not fully characterized yet (7Discher D.E. Janmey P. Wang Y.L. Science. 2005; 310: 1139-1143Crossref PubMed Scopus (4729) Google Scholar). In many previous studies the endothelium acts as a barrier against the invasion of cancer cells (6Al-Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (565) Google Scholar, 8Zijlstra A. Lewis J. Degryse B. Stuhlmann H. Quigley J.P. Cancer Cell. 2008; 13: 221-234Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Furthermore, the endothelium reduces pronouncedly the invasion of cancer cells and, hence, metastasis formation (9Van Sluis G.L. Niers T.M. Esmon C.T. Tigchelaar W. Richel D.J. Buller H.R. Van Noorden C.J. Spek C.A. Blood. 2009; 114: 1968-1973Crossref PubMed Scopus (75) Google Scholar). However, several recent reports propose a novel paradigm in which endothelial cells modulate the invasiveness of several cancer cells by increasing their dissemination through vessels (10Kedrin D. Gligorijevic B. Wyckoff J. Verkhusha V.V. Condeelis J. Segall J.E. van Rheenen J. Nat. Methods. 2008; 5: 1019-1021Crossref PubMed Scopus (307) Google Scholar) or by increasing the invasive capability of cancer cells to migrate into the ECM (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Among these cancer cells is the human breast cancer cell line MDA-MB-231.Although several adhesion molecules have been identified that play a role in tumor-endothelial cell interactions and, hence, metastasis formation, the biomechanical properties of endothelial cells co-cultured with cancer cells are still elusive. There may be altered biomechanical properties of endothelial cells that support the ability of the endothelium to act either as a barrier or as an enhancer for cancer cell invasion. Biomechanical properties have been studied so far only on cancer cells (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Guck J. Schinkinger S. Lincoln B. Wottawah F. Ebert S. Romeyke M. Lenz D. Erickson H.M. Ananthakrishnan R. Mitchell D. Käs J. Ulvick S. Bilby C. Biophys J. 2005; 88: 3689-3698Abstract Full Text Full Text PDF PubMed Scopus (1089) Google Scholar, 13Fritsch A. Höckel M. Kiessling T. Nnetu K.D. Franziska Wetzel F. Zink M. Käs J.A. Nature Physics. 2010; 6: 730-732Crossref Scopus (140) Google Scholar, 14Mierke C.T. Frey B. Fellner M. Herrmann M. Fabry B. J. Cell Science. 2011; 124: 369-383Crossref PubMed Scopus (186) Google Scholar). A main biochemical pathway of the tumor-endothelial interaction has been reported to involve cell adhesion receptors and integrins such as platelet endothelial cell adhesion molecule-1 (PECAM-1) and αvβ3 integrins, respectively (15Voura E.B. Chen N. Siu C.H. Clin. Exp. Metastasis. 2000; 18: 527-532Crossref PubMed Scopus (16) Google Scholar). Integrins are transmembrane adhesion receptors that cluster after activation and assembly of focal adhesions in cell-matrix as well as in cell-cell adhesive interactions (16Geiger B. Bershadsky A. Pankov R. Yamada K.M. Nat. Rev. Mol. Cell Biol. 2001; 2: 793-805Crossref PubMed Scopus (1815) Google Scholar). In addition, integrins forge a link between the ECM and the actin cytoskeleton that can be tensioned by myosin-II motors acting on actin filaments (17Neff N.T. Lowrey C. Decker C. Tovar A. Damsky C. Buck C. Horwitz A.F. J. Cell Biol. 1982; 95: 654-666Crossref PubMed Scopus (195) Google Scholar, 18Damsky C.H. Knudsen K.A. Bradley D. Buck C.A. Horwitz A.F. J. Cell Biol. 1985; 100: 1528-1539Crossref PubMed Scopus (155) Google Scholar, 19Riveline D. Zamir E. Balaban N.Q. Schwarz U.S. Ishizaki T. Narumiya S. Kam Z. Geiger B. Bershadsky A.D. J. Cell Biol. 2001; 153: 1175-1186Crossref PubMed Scopus (1171) Google Scholar). The connection between integrins and the actomyosin cytoskeleton is facilitated through the mechano-coupling focal adhesion and cytoskeletal adaptor protein vinculin (20Mierke C.T. Kollmannsberger P. Zitterbart D.P. Smith J. Fabry B. Goldmann W.H. Biophys. J. 2008; 94: 661-670Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Furthermore, this connection determines the amount of cellular counterforces that maintain the morphology and shape of cells and, hence, provide the cellular stiffness (21Rape A.D. Guo W.H. Wang Y.L. Biomaterials. 2011; 32: 2043-2051Crossref PubMed Scopus (220) Google Scholar). Taken together, until now a biomechanical approach investigating the endothelial barrier breakdown in the presence of co-cultured invasive cancer cells is still elusive.As microrheologic measurements such as magnetic tweezer rheology turn out to be adequate for the identification of cell mechanical properties such as cellular stiffness, in this study endothelial stiffness using magnetic tweezers was measured in co-culture with invasive MDA-MB-231 cells as well as in mono-culture. The results are that highly invasive breast cancer cells influenced the cellular mechanical properties of co-cultured microvascular endothelial cells by lowering the stiffness of endothelial cells. In addition, nanoscale particle tracking method diffusion measurements of actomyosin cytoskeletal-bound beads, which serve as markers, are suitable to determine the actomyosin cytoskeletal remodeling dynamics. Thus, cytoskeletal remodeling dynamics of endothelial cells using nanoscale particle tracking were measured either in mono-culture or in co-culture with highly invasive MDA-MB-231 cells. Here, the cytoskeletal remodeling dynamics of endothelial cells were increased in co-culture with highly invasive cancer cells. These findings indicate that highly invasive breast cancer cells actively altered the biomechanical properties of co-cultured endothelial cells. Hence, these results may provide an explanation for the breakdown of the endothelial barrier function of monolayers.In conclusion, a mechanism in which a decrease in endothelial cell-cell adhesion molecule expression such as PECAM-1 and vascular endothelial-cadherin (VE-cadherin), a decrease in endothelial cell stiffness, and an increase in cytoskeletal remodeling dynamics account for the endothelial barrier breakdown by highly invasive MDA-MB-231 cells was provided in this study.DISCUSSIONCancer cell transendothelial migration and invasion are complex events and depend on biomechanical and biochemical properties of the endothelium and the connective tissue. This study demonstrates that the invasiveness of MDA-MB-231 breast cancer cells is increased in co-culture with human microvascular or macrovascular endothelial cells as indicated by increased numbers of invasive cancer cells and their increased invasion depth. In addition, this article shows that invasive cancer cells altered the biomechanics of endothelial cells.To reveal the function of the endothelium in cancer cell invasion, highly invasive MDA-MB-231 cells and weakly invasive MCF-7 cells were co-cultured with two different types of microvascular endothelial cells. In agreement with a previous report (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), endothelial cells increased the numbers of invasive MDA-MB-231 breast cells as well as their invasion depth in 3D-ECMs. In contrast to MDA-MB-231 cells, MCF-7 breast cancer cells did not transmigrate through an HPMEC monolayer, and only less than 2% of MCF-7 cells were able to migrate through an HUVEC monolayer. These results indicate that the invasiveness of MCF-7 was not enhanced by endothelial cells.Because of these findings, the suggestion was that certain cancer cells such as MDA-MB-231 cells may alter the biomechanical properties of endothelial cells in order to transmigrate and invade 3D-ECMs. Hence, this study focuses on the biomechanical mechanism that leads to higher invasiveness of MDA-MB-231 cells after transendothelial migration. To identify this mechanism, stiffness and cytoskeletal remodeling dynamics of endothelial cells were investigated in co-culture with MDA-MB-231 cancer cells and compared with mono-cultured endothelial cells.Recent results have been shown that single or loosely clustered endothelial as well as a closed endothelial cell monolayer facilitate MDA-MB-231 cell invasion (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Therefore, a co-culture of mixed MDA-MB-231 cells and endothelial cells was used to analyze the mechanical properties of endothelial cells. Here, the cellular stiffness of with MDA-MB-231 cells co-cultured endothelial cells was decreased compared with mono-cultured endothelial cells. This result suggests that MDA-MB-231 cells broke down the endothelial barrier by lowering the cell stiffness. In contrast, the weakly invasive MCF-7 cancer cells were not able to regulate the biomechanical properties of co-cultured endothelial cells (data not shown), suggesting that only highly invasive cancer cells are able to decrease the mechanical stiffness and, hence, increase the deformability of endothelial cells to transmigrate through the endothelial monolayer. Furthermore, this behavior may be a prerequisite to overcome and break down the endothelial barrier.In a previous study, our group found that force fluctuations in an endothelial cell monolayer are widely spread to far distant endothelial cells, suggesting that these force fluctuations are not locally restricted (31Raupach C. Zitterbart D.P. Mierke C.T. Metzner C. Müller F.A. Fabry B. Phys. Rev. E Stat. Nonlin Soft Matter Phys. 2007; 76 (011918)Crossref Scopus (86) Google Scholar). Thus, this study analyzed whether the cytoskeletal remodeling dynamics of endothelial cells are altered during co-culture with MDA-MB-231 cells compared with mono-cultured endothelial cells. Indeed, the MDA-MB-231 cells increased the cytoskeletal remodeling dynamics in co-cultured endothelial cells by 5-fold. In contrast to MDA-MB-231 cancer cells, the non-invasive MCF-7 cancer cells did not alter the cytoskeletal remodeling dynamics of endothelial cells when co-cultured. These results indicate that the ability of highly invasive cancer cells to regulate biomechanical properties of co-cultured endothelial cells may help these cancer cells to transmigrate and invade connective tissue.Previous studies have reported that endothelial cells are exposed to high forces and, hence, respond to them with disruption of their cell-cell adhesions and, subsequently, of the whole endothelial monolayer when neutrophiles or lymphocytes adhere to the endothelium (33Cinamon G. Shinder V. Alon R. Nat. Immunol. 2001; 2: 515-522Crossref PubMed Scopus (347) Google Scholar, 34Rabodzey A. Alcaide P. Luscinskas F.W. Ladoux B. Biophys. J. 2008; 95: 1428-1438Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Hence, neutrophiles and lymphocytes transmit (shear) forces to transmigrate through the endothelium and, finally, into the connective tissue (33Cinamon G. Shinder V. Alon R. Nat. Immunol. 2001; 2: 515-522Crossref PubMed Scopus (347) Google Scholar, 34Rabodzey A. Alcaide P. Luscinskas F.W. Ladoux B. Biophys. J. 2008; 95: 1428-1438Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Therefore, the cell surface expression of cell-cell adhesion molecules such as VE-cadherin and PECAM-1 was analyzed during co-culture with highly invasive MDA-MB-231 cells and weakly invasive MCF-7 cells. Indeed, the expression of VE-cadherin and PECAM-1 on the cell surface of microvascular endothelial cells was reduced after co-culture with highly invasive MDA-MB-231 cells but not with weakly invasive MCF-7 cells, indicating that only the highly invasive cells are able to reduce the cell-cell interactions between neighboring endothelial cells to mediate cancer cell transmigration. The reduction of cell-cell adhesion molecules on endothelial cells and endothelial cell stiffness led to a reduction in endothelial cell barrier function. Whether the reduced cellular stiffness of endothelial cells is mediated by a decrease in cell-cell adhesion molecule expression or vice versa has to be further investigated.For cancer cell transmigration, a dual function of the endothelium was suggested acting either as an enhancer or inhibitor of cancer cell invasion depending on the cancer cell type co-cultured (35Mierke, C. T. (2011) Cell Biochem. Biophys., in press.Google Scholar). Here, it was confirmed that highly invasive MDA-MB-231 breast cancer cells transmigrate through HUVEC and HPMEC monolayers, indicating that their invasive capability was increased in the presence of macrovascular and microvascular endothelial cells. In contrast to previous reports presenting the endothelium as a “passive” barrier for cell invasion (36Verin A.D. Patterson C.E. Day M.A. Garcia J.G. Am. J. Physiol. 1995; 269: L99-L108PubMed Google Scholar, 37Nottebaum A.F. Cagna G. Winderlich M. Gamp A.C. Linnepe R. Polaschegg C. Filippova K. Lyck R. Engelhardt B. Kamenyeva O. Bixel M.G. Butz S. Vestweber D. J. Exp. Med. 2008; 205: 2929-2945Crossref PubMed Scopus (169) Google Scholar), this study shows that the co-culture with highly invasive MDA-MB-231 cells caused biomechanical alterations in endothelial cells that reduced the expression of cell-cell adhesion molecules and, subsequently, the stiffness of endothelial cells. These mechanical alterations may enable cancer cells to transmigrate through an endothelial monolayer and migrate into connective tissue. Thus, the endothelial barrier function seems to be lowered by alterations in endothelial biomechanical properties. These biomechanical results are consistent with an up-regulation of the Erk phosphorylation reported in HUVECs during co-culture with colon cancer cells (38Tremblay P.L. Auger F.A. Huot J. Oncogene. 2006; 25: 6563-6573Crossref PubMed Scopus (117) Google Scholar). Moreover, this study shows that the inhibition of the upstream regulatory protein of Erk MEK abolished the endothelial-facilitated increased invasiveness of α5β1high breast cancer cells. These results suggest that cancer cells may apply forces toward the endothelial cell monolayer to alter endothelial mechanical properties and, hence, facilitate cancer cell transendothelial migration. Indeed, for the transmigration and invasion of highly invasive MDA-MB231 cells, contractile forces are necessary to overcome the endothelial barrier because inhibition of the myosin light chain kinase and subsequently the transmission or generation of contractile forces reduces the number of transmigrating and invading cells, indicating that the endothelial-facilitated increased invasiveness depends on the α5β1 integrin expression. Another supporting point was that α5β1high cells are able to transmit and generate 7-fold higher contractile forces compared with α5β1low cells (14Mierke C.T. Frey B. Fellner M. Herrmann M. Fabry B. J. Cell Science. 2011; 124: 369-383Crossref PubMed Scopus (186) Google Scholar).To reveal by which mechanism cancer cell invasiveness is enhanced by endothelial cells, the transendothelial migration and invasion assay was performed in the presence of embedded FN in 3D-FN-ECMs. As expected, the number of transmigrating and invasive α5β1high cells as well as their invasion depths was increased in the presence of an HPMEC cell monolayer, whereas the invasiveness of α5β1low cells was not affected. These results suggest that FN activates the α5β1 integrins and, subsequently, increases the transmission and generation of contractile forces in α5β1high cells, which further increased their ability to transmigrate and finally to invade. Furthermore, the inhibition of the small GTPases Rho kinase and Rac-1 and of its signaling pathway by PI3K inhibitor revealed that small GTPase signaling may play a role in endothelial-facilitated increased invasiveness of α5β1high cells. In addition, the endothelial-facilitated increased invasiveness of α5β1high cells is not restricted to breast cancer cells, as the invasiveness of α5β1high cells derived from bladder and kidney cancer cells was similarly increased by endothelial cells.Taken together, biophysical measurements may shed light on the biomechanical mechanism that facilitates transendothelial migration of cancer cells. Furthermore, this study indicates that MDA-MB-231 cells break down the endothelial barrier function by lowering cellular stiffness through remodeling of the actin cytoskeleton. In addition, endothelial cells may secrete FN, which then further activates α5β1 integrins on cancer cells by increased transmission or generation of contractile forces and, subsequently, enhances their invasiveness.In conclusion, this study shows that the endothelium was no passive barrier for cancer cell invasion. Instead, the endothelium seems to act cancer cell-specific, as it increased or decreased cancer cell transmigration and invasion of certain cancer cell lines. In addition, biomechanical properties of endothelial cells were altered by a certain type of cancer cells with distinct biomechanical properties, indicating that these biomechanical alterations may play a role in the transendothelial migration process of cancer cells. Finally, this article suggests that biomechanical alterations in endothelial cells evoked by certain cancer cells might provide a biomechanical selection process toward higher invasiveness of cancer cells. In conclusion, biomechanical interactions between highly invasive cancer cells and endothelial cells facilitate the transmigration of cancer cells, further enhance their invasion into connective tissue, and subsequently, may determine the malignancy of tumors. IntroductionThe malignancy of tumors is responsible for most cancer-related deaths. A benign tumor becomes malignant when cancer cells spread from the primary tumor and form metastases (1Frixen U.H. Behrens J. Sachs M. Eberle G. Voss B. Warda A. Löchner D. Birchmeier W. J. Cell Biol. 1991; 113: 173-185Crossref PubMed Scopus (1390) Google Scholar, 2Batlle E. Sancho E. Francí C. Domínguez D. Monfar M. Baulida J. García De Herreros A. Nat. Cell Biol. 2000; 2: 84-89Crossref PubMed Scopus (2149) Google Scholar, 3Cano A. Pérez-Moreno M.A. Rodrigo I. Locascio A. Blanco M.J. del Barrio M.G. Portillo F. Nieto M.A. Nat. Cell Biol. 2000; 2: 76-83Crossref PubMed Scopus (2871) Google Scholar, 4De Craene B. Gilbert B. Stove C. Bruyneel E. van Roy F. Berx G. Cancer Res. 2005; 65: 6237-6244Crossref PubMed Scopus (196) Google Scholar). The process of metastasis can be described in several steps that involve the dissemination of cancer cells from the primary tumor into the extracellular matrix (ECM), 2The abbreviations used are: ECMextracellular matrix3D-ECMthree-dimensional ECMHPMEChuman pulmonary microvascular endothelial cellHDMEChuman dermal microvascular endothelial cellHUVEChuman umbilical vein endothelial cellFNfibronectinPECAM-1platelet endothelial cell adhesion molecule-1VE-cadherinvascular endothelial-cadherinMSDmean square displacementCFDAcarboxyfluorescein diacetateMFImean fluorescence intensityMCmono-culturedCCco-cultured. the invasion of cancer cells through connective tissue, adhesion of cancer cells to the endothelium of blood or lymph vessels, possibly the transmigration of cancer cells through the endothelium (intravasation and/or extravasation), and subsequently, the formation of a secondary tumor in a distant targeted organ (5Steeg P.S. Nat. Med. 2006; 12: 895-904Crossref PubMed Scopus (1629) Google Scholar, 6Al-Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (565) Google Scholar).The impact of endothelial cells on the regulation of cancer cell invasiveness into 3D-ECMs is so far unknown. The regulation of cancer cell invasiveness may be a complex scenario that is not fully characterized yet (7Discher D.E. Janmey P. Wang Y.L. Science. 2005; 310: 1139-1143Crossref PubMed Scopus (4729) Google Scholar). In many previous studies the endothelium acts as a barrier against the invasion of cancer cells (6Al-Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (565) Google Scholar, 8Zijlstra A. Lewis J. Degryse B. Stuhlmann H. Quigley J.P. Cancer Cell. 2008; 13: 221-234Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Furthermore, the endothelium reduces pronouncedly the invasion of cancer cells and, hence, metastasis formation (9Van Sluis G.L. Niers T.M. Esmon C.T. Tigchelaar W. Richel D.J. Buller H.R. Van Noorden C.J. Spek C.A. Blood. 2009; 114: 1968-1973Crossref PubMed Scopus (75) Google Scholar). However, several recent reports propose a novel paradigm in which endothelial cells modulate the invasiveness of several cancer cells by increasing their dissemination through vessels (10Kedrin D. Gligorijevic B. Wyckoff J. Verkhusha V.V. Condeelis J. Segall J.E. van Rheenen J. Nat. Methods. 2008; 5: 1019-1021Crossref PubMed Scopus (307) Google Scholar) or by increasing the invasive capability of cancer cells to migrate into the ECM (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Among these cancer cells is the human breast cancer cell line MDA-MB-231.Although several adhesion molecules have been identified that play a role in tumor-endothelial cell interactions and, hence, metastasis formation, the biomechanical properties of endothelial cells co-cultured with cancer cells are still elusive. There may be altered biomechanical properties of endothelial cells that support the ability of the endothelium to act either as a barrier or as an enhancer for cancer cell invasion. Biomechanical properties have been studied so far only on cancer cells (11Mierke C.T. Zitterbart D.P. Kollmannsberger P. Raupach C. Schlötzer-Schrehardt U. Goecke T.W. Behrens J. Fabry B. Biophys. J. 2008; 94: 2832-2846Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Guck J. Schinkinger S. Lincoln B. Wottawah F. Ebert S. Romeyke M. Lenz D. Erickson H.M. Ananthakrishnan R. Mitchell D. Käs J. Ulvick S. Bilby C. Biophys J. 2005; 88: 3689-3698Abstract Full Text Full Text PDF PubMed Scopus (1089) Google Scholar, 13Fritsch A. Höckel M. Kiessling T. Nnetu K.D. Franziska Wetzel F. Zink M. Käs J.A. Nature Physics. 2010; 6: 730-732Crossref Scopus (140) Google Scholar, 14Mierke C.T. Frey B. Fellner M. Herrmann M. Fabry B. J. Cell Science. 2011; 124: 369-383Crossref PubMed Scopus (186) Google Scholar). A main biochemical pathway of the tumor-endothelial interaction has been reported to involve cell adhesion receptors and integrins such as platelet endothelial cell adhesion molecule-1 (PECAM-1) and αvβ3 integrins, respectively (15Voura E.B. Chen N. Siu C.H. Clin. Exp. Metastas" @default.
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• W2002203108 title "Cancer Cells Regulate Biomechanical Properties of Human Microvascular Endothelial Cells" @default.
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