Tumour-cell invasion and migration: diversity and escape mechanisms

Nature Reviews Cancer - Tập 3 Số 5 - Trang 362-374 - 2003
Peter Friedl1, Katarina Wolf2
1Department of Dermatology, University of Würzburg, Josef‐Schneider‐Str. 2, 97080 Würzburg, Germany
2University of Würzburg

Tóm tắt

Từ khóa


Tài liệu tham khảo

Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

Friedl, P. & Bröcker, E. -B. The biology of cell locomotion within three-dimensional extracellular matrix. Cell. Mol. Life Sci. 57, 41–64 (2000).

Abercrombie, M., Dunn, G. A. & Heath, J. P. The shape and movement of fibroblasts in culture. Soc. Gen. Physiol. Ser. 32, 57–70 (1977).

Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996). The 'bible' for cell migration researchers.

Adams, J. C. Cell-matrix contact structures. Cell. Mol. Life Sci. 58, 371–392 (2001).

Burridge, K. & Chrzanowska-Wodicka, M. Focal adhesions, contractility, and signaling. Annu. Rev. Cell Dev. Biol. 12, 463–519 (1996).

Cramer, L. P. Organization and polarity of actin filament networks in cells: implications for the mechanism of myosin-based cell motility. Biochem. Soc. Symp. 65, 173–205 (1999).

Rohatgi, R. et al. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97, 221–231 (1999).

Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

Otey, C. A. & Burridge, K. Patterning of the membrane cytoskeleton by the extracellular matrix. Semin. Cell Biol. 1, 391–399 (1990).

Zamir, E. et al. Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts. Nature Cell Biol. 2, 191–196 (2000).

Zamir, E. & Geiger, B. Molecular complexity and dynamics of cell-matrix adhesions. J. Cell Sci. 114, 3583–3590 (2001). References 11 and 12 explain the dynamic nature and diversity of cell-matrix interactions. They provide the molecular basis for plasticity and adaptation responses in cell migration.

Regen, C. M. & Horwitz, A. F. Dynamics of beta 1 integrin-mediated adhesive contacts in motile fibroblasts. J. Cell Biol. 119, 1347–1359 (1992).

Smilenov, L. B., Mikhailov, A., Pelham, R. J., Marcantonio, E. E. & Gundersen, G. G. Focal adhesion motility revealed in stationary fibroblasts. Science 286, 1172–1174 (1999).

Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

Rabinovitz, I. & Mercurio, A. M. The integrin alpha6beta4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin-containing motility structures. J. Cell Biol. 139, 1873–1884 (1997).

Leavesley, D. I., Ferguson, G. D., Wayner, E. A. & Cheresh, D. A. Requirement of the integrin beta 3 subunit for carcinoma cell spreading or migration on vitronectin and fibrinogen. J. Cell Biol. 117, 1101–1107 (1992).

Maaser, K. et al. Functional hierarchy of simultaneously expressed adhesion receptors: integrin alpha2beta1 but not CD44 mediates MV3 melanoma cell migration and matrix reorganization within three-dimensional hyaluronan-containing collagen matrices. Mol. Biol. Cell 10, 3067–3079 (1999).

Friedl, P. et al. Migration of highly aggressive MV3 melanoma cells in 3-dimensional collagen lattices results in local matrix reorganization and shedding of alpha2 and beta1 integrins and CD44. Cancer Res. 57, 2061–2070 (1997).

Friedl, P. & Wolf, K. Proteolytic and non–proteolytic migration in tumor cells and leukocytes. Biochem. Soc. Symp. (in the press).

Byers, H. R. & Fujiwara, K. Stress fibers in cells in situ: immunofluorescence visualization with antiactin, antimyosin, and anti-alpha-actinin. J. Cell Biol. 93, 804–811 (1982).

Katoh, K. et al. Rho-kinase-mediated contraction of isolated stress fibers. J. Cell Biol. 153, 569–584 (2001).

Chew, T. L., Wolf, W. A., Gallagher, P. J., Matsumura, F. & Chisholm, R. L. A fluorescent resonant energy transfer-based biosensor reveals transient and regional myosin light chain kinase activation in lamella and cleavage furrows. J. Cell Biol. 156, 543–553 (2002).

Kaibuchi, K., Kuroda, S. & Amano, M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu. Rev. Biochem. 68, 459–486 (1999).

Totsukawa, G. et al. Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J. Cell Biol. 150, 797–806 (2000).

Kamm, K. E. & Stull, J. T. Dedicated myosin light chain kinases with diverse cellular functions. J. Biol. Chem. 276, 4527–4530 (2001).

Somlyo, A. V. et al. Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. FASEB J. 17, 223–234 (2003).

Verkhovsky, A. B., Svitkina, T. M. & Borisy, G. G. Myosin II filament assemblies in the active lamella of fibroblasts: their morphogenesis and role in the formation of actin filament bundles. J. Cell Biol. 131, 989–1002 (1995).

Friedl, P. & Brocker, E. B. in Image Analysis. Methods and Applications 2nd edn (ed. Hader, D. P.) 9–21 (CRC Press, London, 2001).

Palecek, S. P., Loftus, J. C., Ginsberg, M. H., Lauffenburger, D. A. & Horwitz, A. F. Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness. Nature 385, 537–540 (1997).

Ballestrem, C., Hinz, B., Imhof, B. A. & Wehrle-Haller, B. Marching at the front and dragging behind: differential alphaVbeta3-integrin turnover regulates focal adhesion behavior. J. Cell Biol. 155, 1319–1332 (2001).

Potter, D. A. et al. Calpain regulates actin remodeling during cell spreading. J. Cell Biol. 141, 647–662 (1998).

Friedl, P., Zanker, K. S. & Bröcker, E. -B. Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function. Microsc. Res. Tech. 43, 369–378 (1998).

Entschladen, F., Niggemann, B., Zänker, K. S. & Friedl, P. Differential requirement of protein tyrosine kinases and protein kinase C in the regulation of T cell locomotion in three-dimensional collagen matrices. J. Immunol. 159, 3203–3210 (1997).

Friedl, P., Entschladen, F., Conrad, C., Niggemann, B. & Zanker, K. S. CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. Eur. J. Immunol. 28, 2331–2343 (1998).

Yamada, K. M. et al. Monoclonal antibody and synthetic peptide inhibitors of human tumor cell migration. Cancer Res. 50, 4485–4496 (1990).

Filardo, E. J., Brooks, P. C., Deming, S. L., Damsky, C. & Cheresh, D. A. Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. J. Cell Biol. 130, 441–450 (1995).

Flanagan, L. A. et al. Filamin A, the Arp2/3 complex, and the morphology and function of cortical actin filaments in human melanoma cells. J. Cell Biol. 155, 511–517 (2001).

Sameni, M., Moin, K. & Sloane, B. F. Imaging proteolysis by living human breast cancer cells. Neoplasia 2, 496–504 (2001).

Rosenthal, E. L., Hotary, K., Bradford, C. & Weiss, S. J. Role of membrane type 1-matrix metalloproteinase and gelatinase A in head and neck squamous cell carcinoma invasion in vitro. Otolaryngol. Head Neck Surg. 121, 337–343 (1999).

Koblinski, J. E., Ahram, M. & Sloane, B. F. Unraveling the role of proteases in cancer. Clin. Chim. Acta 291, 113–135 (2000).

Hofmann, U. B., Westphal, J. R., van Muijen, G. N. & Ruiter, D. J. Matrix metalloproteinases in human melanoma. J. Invest. Dermatol. 115, 337–344 (2000).

Deryugina, E. I., Bourdon, M. A., Reisfeld, R. A. & Strongin, A. Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix metalloproteinase-2. Cancer Res. 58, 3743–3750 (1998).

Maekawa, K., Sato, H., Furukawa, M. & Yoshizaki, T. Inhibition of cervical lymph node metastasis by marimastat (BB-2516) in an orthotopic oral squamous cell carcinoma implantation model. Clin. Exp. Metastasis 19, 513–518 (2002).

Rudolph-Owen, L. A., Chan, R., Muller, W. J. & Matrisian, L. M. The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res. 58, 5500–5506 (1998).

Sahai, E., Olson, M. F. & Marshall, C. J. Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J. 20, 755–766 (2001).

Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

Itoh, K. et al. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nature Med. 5, 221–225 (1999).

Kaneko, K., Satoh, K., Masamune, A., Satoh, A. & Shimosegawa, T. Myosin light chain kinase inhibitors can block invasion and adhesion of human pancreatic cancer cell lines. Pancreas 24, 34–41 (2002).

Allman, R., Cowburn, P. & Mason, M. In vitro and in vivo effects of a cyclic peptide with affinity for the alpha(nu)beta3 integrin in human melanoma cells. Eur. J. Cancer 36, 410–422 (2000).

Gianelli, G., Falk-Marzillier, J., Schiraldi, O., Stetler-Stevenson, W. G. & Quaranta, V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277, 225–228 (1997).

Alper, O. et al. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J. Natl Cancer Inst. 93, 1375–1384 (2001).

Seftor, R. E. et al. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res. 61, 6322–6327 (2001).

Brooks, P. C. et al. Insulin-like growth factor receptor cooperates with integrin alpha v beta 5 to promote tumor cell dissemination in vivo. J. Clin. Invest. 99, 1390–1398 (1997).

Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002). Comprehensive review on a classic example of plasticity during tumour invasion.

Enterline, H. T. & Cohen, D. R. The ameboid motility of human and animal neoplastic cells. Cancer 3, 1033–1038 (1950).

Wood, S. Jr. Pathogenesis of metastasis formation observed in vivo in the rabbit ear chamber. Arch. Pathol. 66, 550–568 (1958).

Wolf, K. et al. Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160, 267–277 (2003). A novel escape mechanism after the blocking of pericellular proteolysis. By converting to a more 'primitive' amoeboid migration mode, previously proteolytic tumour cells continue to move non-proteolytically by path-finding migration strategies.

Paulus, W., Baur, I., Beutler, A. S. & Reeves, S. A. Diffuse brain invasion of glioma cells requires beta 1 integrins. Lab. Invest. 75, 819–826 (1996).

Polette, M. et al. Association of fibroblastoid features with the invasive phenotype in human bronchial cancer cell lines. Clin. Exp. Metastasis 16, 105–112 (1998).

Tester, A. M., Ruangpani, N., Anderso, R. L. & Thompson, E. W. MMP-9 secretion and MMP-2 activation distinguish invasive and metastatic sublines of a mouse mammary carcinoma system showing epithelial–mesenchymal transition traits. Clin. Exp. Metastasis 18, 553–560 (2000).

Putz, E. et al. Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res. 59, 241–248 (1999).

d'Ortho, M. P. et al. MT1-MMP on the cell surface causes focal degradation of gelatin films. FEBS Lett. 421, 159–164 (1998).

Jeffers, M., Rong, S. & Vande, W. G. Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-Met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol. Cell. Biol 16, 1115–1125 (1996).

Pulyaeva, H. et al. MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin. Exp. Metastasis 15, 111–120 (1997).

Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).

Yoshioka, K., Nakamori, S. & Itoh, K. Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. Cancer Res. 59, 2004–2010 (1999).

Condeelis, J., Jones, J. & Segall, J. E. Chemotaxis of metastatic tumor cells: clues to mechanisms from the Dictyostelium paradigm. Cancer Metastasis Rev. 11, 55–68 (1992).

Yumura, S., Mori, H. & Fukui, Y. Localization of actin and myosin for the study of ameboid movement in Dictyostelium using improved immunofluorescence. J. Cell Biol. 99, 894–899 (1984).

Devreotes, P. N. & Zigmond, S. H. Chemotaxis in eukaryotic cells: a focus on leukocytes and Dictyostelium. Annu. Rev. Cell Biol. 4, 649–686 (1988).

Fey, P., Stephens, S., Titus, M. A. & Chisholm, R. L. SadA, a novel adhesion receptor in Dictyostelium. J. Cell Biol. 159, 1109–1119 (2002).

Farina, K. L. et al. Cell motility of tumor cells visualized in living intact primary tumors using green fluorescent protein. Cancer Res. 58, 2528–2532 (1998). Fascinating in vivo imaging of amoeboid tumour-cell movement.

Friedl, P., Borgmann, S. & Brocker, E. B. Leukocyte crawling through extracellular matrix and the Dictyostelium paradigm of movement: lessons from a social amoeba. J. Leukoc. Biol. 70, 491–509 (2001).

Lewis, W. H. On the locomotion of the polymorphonuclear neutrophiles of the rat in autoplasma cultures. Bull. Johns Hopkins. Hosp. 4, 273–279 (1934). One of the first papers showing shape change as a mechanism to bypass ECM barriers.

Werr, J., Xie, X., Hedqvist, P., Ruoslahti, E. & Lindbom, L. Beta1 integrins are critically involved in neutrophil locomotion in extravascular tissue in vivo. J. Exp. Med. 187, 2091–2096 (1998).

Brakebusch, C. et al. Beta1 integrin is not essential for hematopoiesis but is necessary for the T cell-dependent IgM antibody response. Immunity 16, 465–477 (2002).

Haston, W. S., Shields, J. M. & Wilkinson, P. C. Lymphocyte locomotion and attachment on two-dimensional surfaces and in three-dimensional matrices. J. Cell Biol. 92, 747–752 (1982). Provides the first example of 'non-adhesive' migration in 3D collagen lattices.

Mandeville, J. T., Lawson, M. A. & Maxfield, F. R. Dynamic imaging of neutrophil migration in three dimensions: mechanical interactions between cells and matrix. J. Leukoc. Biol. 61, 188–200 (1997).

Verschueren, H., de Baetselier, P. & Bereiter-Hahn, J. Dynamic morphology of metastatic mouse T-lymphoma cells invading through monolayers of 10T1/2 cells. Cell Motil. Cytoskeleton 20, 203–214 (1991).

Rintoul, R. C. & Sethi, T. The role of extracellular matrix in small-cell lung cancer. Lancet Oncol. 2, 437–442 (2002).

Falcioni, R. et al. Expression of beta 1, beta 3, beta 4, and beta 5 integrins by human lung carcinoma cells of different histotypes. Exp. Cell Res. 210, 113–122 (1994).

Jaspars, L. H., Bonnet, P., Bloemena, E. & Meijer, C. J. Extracellular matrix and beta 1 integrin expression in nodal and extranodal T-cell lymphomas. J. Pathol. 178, 36–43 (1996).

Kraus, A. C. et al. In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 21, 8683–8695 (2002).

Jacques, T. S. et al. Neural precursor cell chain migration and division are regulated through different beta1 integrins. Development 125, 3167–3177 (1998).

El Fahime, E., Torrente, Y., Caron, N. J., Bresolin, M. D. & Tremblay, J. P. In vivo migration of transplanted myoblasts requires matrix metalloproteinase activity. Exp. Cell Res. 258, 279–287 (2000).

Page, D. L., Anderson, T. J. & Sakamoto, G. in Diagnostic Histopathology of the Breast 219–222 (Churchill Livingstone, New York, 1987).

Pitts, W. C. et al. Carcinomas with metaplasia and sarcomas of the breast. Am. J. Clin. Pathol. 95, 623–632 (1991).

Sood, A. K. et al. Molecular determinants of ovarian cancer plasticity. Am. J. Pathol. 158, 1279–1288 (2001).

Seftor, E. A. et al. Molecular determinants of human uveal melanoma invasion and metastasis. Clin. Exp. Metastasis 19, 233–246 (2002).

Davidson, L. A. & Keller, R. E. Neural tube closure in Xenopus laevis involves medial migration, directed protrusive activity, cell intercalation and convergent extension. Development 126, 4547–4556 (1999).

Klinowska, T. C. et al. Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. Dev. Biol. 215, 13–32 (1999).

Simian, M. et al. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development 128, 3117–3131 (2001).

Hiraoka, N., Allen, E., Apel, I. J., Gyetko, M. R. & Weiss, S. J. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95, 365–377 (1998).

Collen, A. et al. Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix. Blood 101, 1810–1817 (2003).

Vaughan, R. B. & Trinkaus, J. P. Movements of epithelial cell sheets in vitro. J. Cell Sci. 1, 407–413 (1966).

Kolega, J. The movement of cell clusters in vitro: morphology and directionality. J. Cell Sci. 49, 15–32 (1981). Provides a detailed description of how clustered cells move as a functional unit.

Friedl, P. et al. Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res. 55, 4557–4560 (1995).

Nabeshima, K. et al. Ultrastructural study of TPA-induced cell motility: human well-differentiated rectal adenocarcinoma cells move as coherent sheets via localized modulation of cell–cell adhesion. Clin. Exp. Metastasis 13, 499–508 (1995).

Hegerfeldt, Y., Tusch, M., Brocker, E. B. & Friedl, P. Collective cell movement in primary melanoma explants: plasticity of cell-cell interaction, β1-integrin function, and migration strategies. Cancer Res. 62, 2125–2130 (2002). First example of collective–amoeboid transition after blocking of β1-integrins — another escape mechanism.

Nabeshima, K. et al. Front-cell-specific expression of membrane-type 1 matrix metalloproteinase and gelatinase A during cohort migration of colon carcinoma cells induced by hepatocyte growth factor/scatter factor. Cancer Res. 60, 3364–3369 (2000).

Bell, C. D. & Waizbard, E. Variability of cell size in primary and metastatic human breast carcinoma. Invasion Metastasis 6, 11–20 (1986).

Nabeshima, K., Inoue, T., Shimao, Y., Kataoka, H. & Koono, M. Cohort migration of carcinoma cells: differentiated colorectal carcinoma cells move as coherent cell clusters or sheets. Histol. Histopathol. 14, 1183–1197 (1999).

Ackerman, A. B. & Ragaz, A. in The Lives of Lesions (ed. Ackerman, A. B.) 147–158 (Masson Publishers, New York, 1984).

Hashizume, R., Koizumi, H., Ihara, A., Ohta, T. & Uchikoshi, T. Expression of beta-catenin in normal breast tissue and breast carcinoma: a comparative study with epithelial cadherin and alpha-catenin. Histopathology 29, 139–146 (1996).

Madhavan, M. et al. Cadherins as predictive markers of nodal metastasis in breast cancer. Mod. Pathol. 14, 423–427 (2001).

Byers, S. W., Sommers, C. L., Hoxter, B., Mercurio, A. M. & Tozeren, A. Role of E-cadherin in the response of tumor cell aggregates to lymphatic, venous and arterial flow: measurement of cell–cell adhesion strength. J. Cell Sci. 108, 2053–2064 (1995).

Brandt, B. et al. Isolation of prostate-derived single cells and cell clusters from human peripheral blood. Cancer Res. 56, 4556–4561 (1996).

Pishvaian, M. J. et al. Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res. 59, 947–952 (1999).

Hsu, M., Andl, T., Li, G., Meinkoth, J. L. & Herlyn, M. Cadherin repertoire determines partner-specific gap junctional communication during melanoma progression. J. Cell Sci. 113, 1535–1542 (2000).

Moll, R., Mitze, M., Frixen, U. H. & Birchmeier, W. Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am. J. Pathol. 143, 1731–1742 (1993).

Klein, C. E., Steinmayer, T., Kaufmann, D., Weber, L. & Brocker, E. B. Identification of a melanoma progression antigen as integrin VLA-2. J. Invest. Dermatol. 96, 281–284 (1991).

Trikha, M. et al. The high affinity alphaIIb beta3 integrin is involved in invasion of human melanoma cells. Cancer Res. 57, 2522–2528 (1997).

Strobel, T. & Cannistra, S. A. Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro. Gynecol. Oncol. 73, 362–367 (1999).

Chao, C., Lotz, M. M., Clarke, A. C. & Mercurio, A. M. A function for the integrin alpha6beta4 in the invasive properties of colorectal carcinoma cells. Cancer Res. 56, 4811–4819 (1996).

Cress, A. E., Rabinovitz, I., Zhu, W. & Nagle, R. B. The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression. Cancer Metastasis Rev. 14, 219–228 (1995).

Danen, E. H. J. et al. Regulation of integrin-mediated adhesion to laminin and collagen in human melanocytes and in non-metastatic and highly metastatic human melanoma cells. Int. J. Cancer 54, 315–321 (1993).

Zutter, M. M., Santoro, S. A., Staatz, W. D. & Tsung, Y. L. Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proc. Natl Acad. Sci. USA 92, 7411–7415 (1995).

Schirner, M. et al. Integrin alpha5beta1: a potent inhibitor of experimental lung metastasis. Clin. Exp. Metastasis 16, 427–435 (1998).

Mignatti, P., Robbins, E. & Rifkin, D. B. Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 47, 487–498 (1986).

Kurschat, P. et al. Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. J. Biol. Chem. 274, 21056–21062 (1999).

Ntayi, C., Lorimier, S., Berthier-Vergnes, O., Hornebeck, W. & Bernard, P. Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices. Exp. Cell Res. 270, 110–118 (2001).

Hotary, K., Allen, E., Punturieri, A., Yana, I. & Weiss, S. J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149, 1309–1323 (2000). Together with references 63 and 159, this paper shows that MT1-MMP is the most important collagenase in invading tumour cells. They formally prove the concept that pericellular proteolysis contributes to invasion.

Wang, X., Fu, X., Brown, P. D., Crimmin, M. J. & Hoffman, R. M. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 54, 4726–4728 (1994).

Maki, H. et al. Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11. Clin. Exp. Metastasis 19, 519–526 (2002).

Kruger, A. et al. Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res. 61, 1272–1275 (2001).

Della, P. P. et al. Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. Anticancer Res. 19, 3809–3816 (1999).

Zucker, S., Cao, J. & Chen, W. T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19, 6642–6650 (2000).

Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2, 657–672 (2002). References 127–129 summarize and explain the failure of clinical trials of matrix metalloproteinase inhibitors in late-stage cancer patients. It sets the scene for future work in the MMP field.

Lochter, A., Navre, M., Werb, Z. & Bissell, M. J. alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression. Mol. Biol. Cell 10, 271–282 (1999).

Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).

Sakkab, D. et al. Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. J. Biol. Chem. 275, 10772–10778 (2000).

Quirt, I. et al. Phase II study of marimastat (BB-2516) in malignant melanoma: a clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trials Group. Invest. New Drugs 20, 431–437 (2002).

Bonomi, P. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Semin. Oncol. 29, 78–86 (2002).

Harbeck, N., Kates, R. E. & Schmitt, M. Clinical relevance of invasion factors urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 for individualized therapy decisions in primary breast cancer is greatest when used in combination. J. Clin. Oncol. 20, 1000–1007 (2002).

Leung-Toung, R., Li, W., Tam, T. F. & Karimian, K. Thiol-dependent enzymes and their inhibitors: a review. Curr. Med. Chem. 9, 979–1002 (2002).

Fassler, R. & Meyer, M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 9, 1896–1908 (1995).

Fassler, R. et al. Lack of beta 1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J. Cell Biol. 128, 979–988 (1995). Together with references 35, 76 and 77, this paper shows that β1 integrins can be dispensable for cell movement and positioning in 3D tissue structures.

Lombardi, L. et al. Ultrastructural cytoskeleton alterations and modification of actin expression in the NIH/3T3 cell line after transformation with Ha-ras-activated oncogene. Cell Motil. Cytoskeleton 15, 220–229 (1990).

Dartsch, P. C., Ritter, M., Haussinger, D. & Lang, F. Cytoskeletal reorganization in NIH 3T3 fibroblasts expressing the Ras oncogene. Eur. J. Cell Biol. 63, 316–325 (1994).

Khosravi-Far, R. et al. Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras. Mol. Cell. Biol. 14, 6848–6857 (1994).

Qiu, R. G., Chen, J., McCormick, F. & Symons, M. A role for Rho in Ras transformation. Proc. Natl Acad. Sci. USA 92, 11781–11785 (1995).

Whittard, J. D. & Akiyama, S. K. Activation of beta1 integrins induces cell–cell adhesion. Exp. Cell Res. 263, 65–76 (2001).

Robinson, E. E., Zazzali, K. M., Corbett, S. A. & Foty, R. A. Alpha5beta1 integrin mediates strong tissue cohesion. J. Cell Sci. 116, 377–386 (2003).

Whittard, J. D. et al. E-cadherin is a ligand for integrin alpha2beta1. Matrix Biol. 21, 525–532 (2002).

Hynes, R. O. & Zhao, Q. The evolution of cell adhesion. J. Cell Biol. 150, F89–F96 (2000). Insightful overview of how adhesion receptors evolved in the context of increasing tissue complexity and segregation.

Blanchoin, L. et al. Direct observation of dendritic actin filament networks nucleated by Arp2/3 complex and WASP/Scar proteins. Nature 404, 1007–1011 (2000).

Nobes, C. D. & Hall, A. Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

Ren, X. D. et al. Physical association of the small GTPase Rho with a 68-kDa phosphatidylinositol 4-phosphate 5-kinase in Swiss 3T3 cells. Mol. Biol. Cell 7, 435–442 (1996).

Leopoldt, D. et al. Gbetagamma stimulates phosphoinositide 3-kinase-gamma by direct interaction with two domains of the catalytic p110 subunit. J. Biol. Chem. 273, 7024–7029 (1998).

Tsutsumi, S., Gupta, S. K., Hogan, V., Collard, J. G. & Raz, A. Activation of small GTPase Rho is required for autocrine motility factor signaling. Cancer Res. 62, 4484–4490 (2002).

Miyamoto, S. et al. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J. Cell Biol. 131, 791–805 (1995).

Calderwood, D. A., Shattil, S. J. & Ginsberg, M. H. Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J. Biol. Chem. 275, 22607–22610 (2000).

Degani, S. et al. The integrin cytoplasmic domain-associated protein ICAP-1 binds and regulates Rho family GTPases during cell spreading. J. Cell Biol. 156, 377–387 (2002).

DeMali, K. A., Barlow, C. A. & Burridge, K. Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. J. Cell Biol. 159, 881–891 (2002).

Schwartz, M. A. & Shattil, S. J. Signaling networks linking integrins and Rho family GTPases. Trends Biochem. Sci. 25, 388–391 (2000).

Ilic, D. et al. Reduced cell motility and anhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544 (1995).

Mueller, S. C. et al. A novel protease-docking function of integrin at invadopodia. J. Biol. Chem. 274, 24947–24952 (1999).

Ohuchi, E. et al. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 272, 2446–2451 (1997).

Dumin, J. A. et al. Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen. J. Biol. Chem. 276, 29368–29374 (2001).

Brooks, P. C., Silletti, S., von Schalscha, T. L., Friedlander, M. & Cheresh, D. A. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 92, 391–400 (1998).

Ellerbroek, S. M., Wu, Y. I., Overall, C. M. & Stack, M. S. Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J. Biol. Chem. 276, 24833–24842 (2001).

Galvez, B. G., Matias-Roman, S., Yanez-Mo, M., Sanchez-Madrid, F. & Arroyo, A. G. ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells. J. Cell Biol. 159, 509–521 (2002).

Tam, E. M., Wu, Y. I., Butler, G. S., Stack, M. S. & Overall, C. M. Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage. J. Biol. Chem. 277, 39005–39014 (2002).

Fukata, Y., Amano, M. & Kaibuchi, K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol. Sci. 22, 32–39 (2001).

Wear, M. A., Schafer, D. A. & Cooper, J. A. Actin dynamics: assembly and disassembly of actin networks. Curr. Biol. 10, R891–R895 (2000).

Zeng, L. et al. PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J. Cell Biol. 160, 137–146 (2003).

Pfaff, M., Du, X. & Ginsberg, M. H. Calpain cleavage of integrin beta cytoplasmic domains. FEBS Lett. 460, 17–22 (1999).

Moss, M. L. & Lambert, M. H. Shedding of membrane proteins by ADAM family proteases. Essays Biochem. 38, 141–153 (2002).

Carragher, N. O., Levkau, B., Ross, R. & Raines, E. W. Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. J. Cell Biol. 147, 619–630 (1999).

Bretscher, M. S. Getting membrane flow and the cytoskeleton to cooperate in moving cells. Cell 87, 601–606 (1996).

Firtel, R. A. & Meili, R. Dictyostelium: a model for regulated cell movement during morphogenesis. Curr. Opin. Genet. Dev. 10, 421–427 (2000).

Scotton, C. J. et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 62, 5930–5938 (2002).

Price, J. T., Tiganis, T., Agarwal, A., Djakiew, D. & Thompson, E. W. Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3′-kinase and phospholipase C-dependent mechanism. Cancer Res. 59, 5475–5478 (1999).

Sawada, K. et al. Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of Rho. Cancer Res. 62, 6015–6020 (2002).

Doerr, M. E. & Jones, J. I. The roles of integrins and extracellular matrix proteins in the insulin-like growth factor 1-stimulated chemotaxis of human breast cancer cells. J. Biol. Chem. 271, 2443–2447 (1996).

Guvakova, M. A. & Surmacz, E. The activated insulin-like growth factor 1 receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin. Exp. Cell Res. 251, 244–255 (1999).