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Physiology 20: 194-200, 2005; doi:10.1152/physiol.00009.2005
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Physiology, Vol. 20, No. 3, 194-200, June 2005
© 2005 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Physiological Mechanisms of Tumor-Cell Invasion and Migration

David H. Geho, Russell W. Bandle, Timothy Clair and Lance A. Liotta

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

gehod{at}mail.nih.gov


   Abstract
 
Recent advances in understanding the complex biology of the microenvironment that underlies tumor invasion and migration have revealed novel and promising therapeutic targets. Pharmacological blockade of intra- and extracellular signaling events that regulate migration and survival of multiple cell types may disrupt the host-tumor conspiracy that allows escape from normal developmental regulation.


   Introduction
Top
 Introduction
Tumor Cell Migration Through...
 Defining Molecular Markers of...
 References
 
Numerous molecular hurdles stand between a newly invasive tumor cell and its distant new home in another organ. The rigor of the journey is reflected by the finding that <0.05% of circulating tumor cells are actually able to become stable metastases (34). The metastatic sequence is understood to involve detachment of cells within a primary tumor, local migration and invasion of stromal tissue, intravasation and transit through blood vessels, capillary bed arrest and extravasation, further local crawling and invasion, attachment, formation of micrometastases, survival, perhaps dormancy, and eventually further proliferation (FIGURE 1Go) (6, 64).



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  		FIGURE 1. The metastatic sequence

 
To overcome this remarkable set of challenges, the invasive cancer cell must borrow a molecular apparatus, or infrastructure, that normally enables important physiological functions, such as morphogenesis (58), neurogenesis (66), and angiogenesis (14). These examples of invasion are under exquisite control and facilitate the development and homeostasis of an organism. In marked contrast, metastatic tumor cells prey upon these molecular systems, often leading to organismal demise (37). Numerous interactions underlie this complicated progression as cancer cells conspire with their local environment to grow, survive, and metastasize (FIGURE 2Go). Each of the steps involved in tumor metastasis requires numerous specific molecular interactions contributed by the tumor cell and the surrounding extracellular matrix (ECM) and stromal cells (35). These interactions are mediated by contact between the cell and the ECM, by direct cell-cell contact, and by secreted factors.



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  		FIGURE 2. Stromal cells and ECM components actively contribute to an environment of metastatic potential
Through cell-cell contacts, cell-matrix contacts, and soluble mediators, complex communications initiate and sustain the invasion and migration of tumor cells.

 

   Tumor Cell Migration Through Tissue Microenvironments
Top
 Introduction
 Tumor Cell Migration Through...
Defining Molecular Markers of...
 References
 
Three-dimensional (3-D) molecular contacts, contributed by the basement membrane, ECM, and adjacent cells, provide an architectural context within which a normal cell functions. Adhesive structures are physical connections between the cytoskeleton (CSK) and the ECM (an extracellular-matrix connection) or between the CSK and the CSK of other cells (a cell-cell connection). There are several adhesion receptor families, including selectins, syndecans, the immunoglobulin cell adhesion molecules, cadherins, and integrins. The best-studied adhesion receptors, and of particular interest in migration, are the integrins. These are heterodimeric transmembrane protein structures that bind specific extracellular sites on the ECM and specific intracellular CSK adapter proteins (21).

As integrins form connections with the extracellular environment, they provide structural support. They also mediate intracellular signaling through the activation of focal adhesion kinase (22). It is not surprising that the native ECM of a normal cell is a requisite for survival. Indeed, removal of a cell from its supportive matrix can cause that cell to die, also called "anoikis" (18). Recent work has demonstrated that expression of TrkB protein, a neurotrophic receptor, enables a cell to survive, avoiding anoikis, when it has been removed from its native matrix (11). This protein enables the tumor cell to retool its signaling machinery, stimulating the phosphatidylionolistol-3-OH and AKT/PKB kinases, leading to inhibition of caspases, key mediators of anoikis.

For a tumor cell to metastasize, it must pass through surrounding stromal elements as it migrates toward a lymph or blood vessel. One important class of molecules within the invasion front is that of the matrix metalloproteinase (MMP). The localized and tightly regulated enzymatic remodeling of stromal tissue by MMPs is an interesting example of collaboration among cell types: MMPs can be secreted by neighboring cells and can become localized and activated on the surface of migrating tumor or endothelial cells (3, 5, 38, 45, 63). Proteolytic activity facilitates migration in several ways. Physical barriers of dense matrix are removed; latent proteases, growth factors, and chemotactic agents (and their receptors) can be activated; integrin-binding sites on the ECM can become exposed and available to transmit migratory and survival signals (4, 9, 42); and bioactive fragments of the ECM itself are produced. These are zinc-binding enzymes that are secreted as proenzymes and are activated in the ECM through the cleavage of an 80-amino-acid sequence located in the amino-terminal domain (15, 40, 54). Groupings within the MMPs have emerged, yielding the stromelysins (which cleave fibronectin, proteoglycans, and nonhelical regions of type IV collagen), the interstitial collagenases (which degrade triple-helical regions of fibrillar collagens types I, II, III, VII, VIII, and X), and the gelatinases (which degrade denatured collagen; native collagen types IV, V, VII, IX, and X; fibronectin; and elastin) (50). Control of MMP function is maintained by the endogenous inhibitors of the MMPs, called the tissue inhibitors of metalloproteinases.

Once ECM barriers at the invasion front have been cleared through proteolytic degradation, the metastatic cancer cell must generate an invasive machinery (32).

Cell migration, including the migration of tumor cells during several steps in the metastatic process, is a response to environmental cues and results in the orderly rearrangement of adhesive structures that connect the cell to the ECM. Any contribution to the microenvironment, from either tumor or stromal cells, that affects the character of the ECM itself, the expression and activation of various adhesive structures, or the complement of soluble regulatory factors available can influence the migration response. Although some of these interactions are known, it is likely that many of the specific molecules responsible remain unidentified.

Environmental cues for locomotion, mediated either by integrins or by receptors for soluble chemotactic agents, are integrated into a coordinated cellular response by the same signal-transducing, information-processing network that mediates proliferative, stress, and survival responses (FIGURE 3Go). The engagement of an integrin with its ligand can be accompanied by recruitment of intracellular signaling components, integrin clustering, and signaling responses that include tyrosine phosphorylation within adhesion complexes, activation of MAP kinases and the lipid kinase phosphatidylinositol 3-kinase, and activation of Rho family GTPases. Cell-ECM adhesion is required for efficient transmission of receptor tyrosine kinase-mediated or G protein-coupled receptor-mediated signaling responses, and physical and functional associations of integrins with these other receptor types have been detected (10, 21, 65). Environmental cues from the ECM and from soluble factors converge at integrin-coordinated intracellular signaling scaffolds (26).



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  		FIGURE 3. Tumor cell transformation
As a tumor cell transforms into a migratory cell, the molecular machinery that processes cellular signals for proliferation and survival responses also regulates the formation of migratory behaviors.

 
Studies on the movement of cells on two-dimensional (2-D) substrata describe migration as a multistep, cyclical process involving morphological polarization of the cell, membrane extension, formation of cell-substratum attachments, forward movement of the cell body, and release of attachments at the trailing edge of the cell. The forces responsible for these activities are the polymerization of actin and the myosin-driven contraction of the CSK. De-adhesion can be rate limiting, and maximum migration speeds are achieved at intermediate adhesive strengths, indicating the importance of both adhesion and de-adhesion (24, 27, 30). Rho family GTPases act as central regulators of cytoskeletal dynamics, and the levels of their activated (GTP-bound) states are regulated by a balance between activation by exchange factors (called GEFs) that facilitate replacement of GDP by GTP and inactivation by GTPase-activating proteins (called GAPs) that attenuate signals by stimulating hydrolysis of bound GTP. In cultured fibroblasts (23), activated RhoA stimulates the formation of actin stress fibers and mature elongated focal adhesions, effects that depend on contractile force within the CSK (7). This effect is mediated in part through the Rho effector, Rho kinase, which stimulates sustained CSK contraction by inhibiting myosin light-chain phosphatase (19, 28). Activated Cdc42 stimulates actin polymerization and the formation of thin membrane protrusions called filopodia, and activated Rac stimulates the processes of membrane ruffling and cell spreading that result in formation of actin-rich lamellipodial protrusions. Rho family GTPase activities regulate other types of dynamic adhesive structures, including cadherin-based adherens junctions between cells, and Rac and Rho activities are antagonistic in some contexts (1, 13). The relative activities of the various Rho family GTPases, through their effects on CSK dynamics at specific subcellular locations, mediate transitions between epithelial and mesenchymal phenotypes and integrate environmental information to produce a coordinated migration response.

Integrin-mediated attachment of these cell protrusions to the ECM can occur in a preferred direction, following gradients of ECM binding sites and resulting in directed spreading, called haptotaxis. Alternatively, or in combination with ECM cues, concentration gradients of soluble motogens can morphologically polarize a cell and stimulate directed migration, called chemotaxis. In combination, these activities can result in contact-guided migration along oriented tissue fibers. Tumor invasion occurs in the 3-D ECM, and migration mechanisms used by cells in that environment may not be apparent in 2-D systems. Cell migration, in experimental 3-D systems of various composition, retains the principle elements of haptotactic migration, including clustering of integrins at adhesion sites and detachment of cells by either release or internalization of integrins. There are differences, however, that are not fully understood and that may be significant, because cells must use additional strategies to overcome matrix resistance (16). Cells migrating in 3-D matrices lack stress fibers, focal adhesions, and large lamellipodia but display cylindrical pseudopodia with microspikes and small lamellipodial structures. It is possible that the same contractile forces that inhibit migration by focal adhesion formation on planar surfaces may be promigratory in a 3-D environment where the adhesion sites are more dispersed. Some mammalian cells, including embryonic stem cells, T and B cells, neutrophils, monocytes, and some tumor cells, are capable of an ameboid type of migration that is characterized by a lack of focal contacts and integrin clusters and by the presence of pseudopod protrusion and retraction that is, in contrast to integrin-guided protrusions, independent of attachment.

The above discussion is based on the behavior of individual cells, but histological observations indicate the presence of invasive clusters of cells in epithelial tumors as well as in blood and lymph vessels. In 3-D collagen matrices, the leading edge of such clusters is comprised of highly motile "pathfinder" cells, whereas the cells in the trailing edge are passive, suggesting that tumor cell clusters may be organized as coherent tissue that contains cells with specialized (e.g., invasive) functions (17, 36, 51).

Environmental complexity
As described, migration and invasion of cells in tumor stroma result from cooperation among protrusive, adhesive, contractile, and proteolytic mechanisms and occurs under the combined influence that tumor and stromal cells have on the content and architecture of the ECM as well as on the autocrine and paracrine production and activation of proteinases and chemotactic factors. This complex microenvironment contains migration-stimulating factors such as scatter factor/hepatocyte growth factor produced by fibroblasts, vascular endothelial growth factor and basic fibroblast growth factor (bFGF) produced by tumor cells, MMPs and urokinase-type plasminogen activator produced by fibroblasts and endothelial cells, transforming growth factor (TGF)-ß produced by tumor cells or released from the ECM by proteinase activity, epithelial growth factor and platelet-derived growth factor produced by tumor cells, cytokines produced by inflammatory cells, and chemokines from inflammatory and stromal cells (35).

Underscoring the role of the tumor microenvironment in invasive and metastatic behavior, stromal matrix and cells induce motility as well. Motility factors within the ECM include vitronectin (2), fibronectin and laminin (39), type I collagen (60), type IV collagen (29), and thrombospondin (59). Motility factors secreted by stromal cells include histamine (61), insulin-like growth factor-I (55), and interleukin (IL)-8 (62). These motility factors have also been described as homing factors, because tumor cells are attracted to the organs that produce them. For example, chemokines secreted by various tissues may be chemotactic for circulating tumor cells, such as metastatic breast cancer, that bear the matching chemokine receptor (44). Motility factors intrinsic to tumor cells are the autocrine motility factors such as hepatocyte growth factor (20), insulin-like growth factor-II (12), and autotaxin (ATX) (56).

The involvement of ATX in tumor metastasis demonstrates a complexity within tumor-host microenvironments, resulting in technological challenges for early cancer detection and therapeutic design. ATX is a widely expressed secreted enzyme that was initially discovered as a melanoma cell autocrine motility factor. ATX stimulates the migration of a variety of cells, including cancer cells, fibroblasts, and vascular smooth muscle cells. ATX promotes aggressive behavior in some tumors through enhancement of invasive, migratory, and angiogenic potentials (FIGURE 4Go). ATX is overexpressed in various cancers, and its expression can be regulated by several growth and biological factors, including retinoic acid, interferon-{gamma}, IL-1, IL-4, and TGF-ß (41, 43).



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  		FIGURE 4. Autotaxin
Autotaxin (ATX) is an example of a single molecular factor that influences multiple aspects of metastasis.

 
Recent discoveries that ATX can catalyze the production of two highly potent bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) from the precursors lysophosphatidylcholine and sphingosylphosphorylcholine, respectively, have provided insight into ATX activity (52) (FIGURE 5Go). LPA and S1P are potent mediators of diverse biological functions. For example, through specific G protein-coupled membrane receptors, extracellular LPA and S1P invoke signaling cascades involving adenylate cyclase, phosphatidylinositol 3-kinase, Ras-MAPK, phospholipase C, Akt/PKB, c-Src tyrosine kinase, the small GTPases Rac and Rho, phospholipase D, and p125 focal adhesion kinase (25). These signaling pathways control numerous events important for normal cellular function, tumor invasion, and metastasis. LPA can modulate cell proliferation, survival, migration, and invasion through multiple pathways. For example, LPA can mediate cytoskeletal organization through focal adhesion formation and integrin activation, N-cadherin-mediated cell clustering, wound healing through platelet aggregation, vascular remodeling, and upregulation of MMPs, as well as neurite retraction (41). S1P stimulates survival signaling and promotes angiogenesis by stimulating endothelial cell motility and tube formation. S1P also inhibits some tumor and leukocyte cell migration (57).



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  		FIGURE 5. Migratory behavior of tumor cells
The commitment toward migratory behavior involves contributions from extracellular, plasma membrane, and intracellular molecular structures. ATX provides one example of how the same molecule can induce different cellular behaviors depending on the cellular phenotype of the signal-receiving cell.

 
Expression of ATX in Ras-transformed fibroblasts augments their in vitro invasive potential as well as the size, number, and vascularity of tumors formed in mice (16). Inclusion of ATX, or ATX-secreting cells, elicits an angiogenic response in Matrigel plugs inserted subcutaneously in mice (46), including the formation of blood vessels that contain both endothelial cells and pericytes. ATX stimulates a tubulogenic response in endothelial cells but does not stimulate a strong migration response in chemotaxis assays. The angiogenic activity of ATX may affect nonendothelial cell targets, including pericytes that can stabilize new vessels. Vascular smooth muscle cells, as well as endothelial cells stimulated with the angiogenic factor bFGF, secrete ATX, raising the possibility that three different cell types contribute to the angiogenic response by secreting ATX into a mutually attractive environment. The biological effects of ATX depend on its enzymatic activity (31), and in vitro migration experiments indicate that divergent migration responses (stimulatory or inhibitory) to ATX/LPA and S1P can be regulated by lysophospholipid receptor-type expression and the availability of alternative substrates for ATX (8, 47). The local expression of ATX and its substrates provides additional regulatory and signaling complexity in the tumor microenvironment. ATX may also be an extracellular target for pharmacological therapy that awaits the design of specific enzyme inhibitors.


   Defining Molecular Markers of Metastatic Potential
Top
 Introduction
 Tumor Cell Migration Through...
 Defining Molecular Markers of...
References
 
In a cloak-and-dagger scenario, the metastatic tumor cell capitalizes on physiological mechanisms to create and sustain a pathophysiological state. The growing understanding of the varied molecular terrain that a metastatic tumor cell traverses presents a rich source of potential prognostic indicators, or biomarkers, as well as therapeutic targets. The dependence of tumor cells on the surrounding ECM and stromal cells highlights the importance of studying the molecular profiles of cells within their native microenvironments. One recent study using protein microarray technology (48) compared the molecular profiles generated between prostatic carcinoma tissue microdissected by laser capture microdissection and cell lines of the same tumor type. The differences between the two profiles demonstrate the need to develop tools that allow the pathologist and basic scientist to have access to primary molecular material from cancer specimens. Moreover, as the steps of metastasis are reviewed, the role of posttranslationally modified proteins in tumor invasion and metastasis, such as cleavage and phosphorylation, is becoming more apparent.

With protein microarrays, the presence of known protein isoforms are probed in tumor cells and/or surrounding stromal cells. Protein microarray formats allow protein lysates from pure cell populations, procured using laser capture microdissection, to be arrayed on a substrate for subsequent probing using antibodies (33). This type of array format has been used to characterize molecular signaling pathway alterations that occur within varying stages of prostate cancer (49). In another, more recent study using protein microarray technology (53), primary and metastatic tumors from the same patients with ovarian cancer have been examined. The proteomic signaling pathways are markedly divergent between the primary tumor cells and the metastatic tumor cells. Intriguing questions arise from such findings. Namely, is the divergent cellular behavior due to the effects of differing microenvironments that surround the primary and metastatic tumor cells? Or rather, is the altered proteomic signaling profile attributable to the development of a divergent clonal population of metastatic tumor cells that emerges under selective pressures? Molecular profiling of each stage of a tumor’s life cycle will provide insight into these questions. Furthermore, these kinds of proteomic studies will reveal potential targets for therapeutic intervention.


   References
Top
 Introduction
 Tumor Cell Migration Through...
 Defining Molecular Markers of...
 References
 

  1. Arthur WT and Burridge K. RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol Biol Cell 12: 2711–2720, 2001.[Abstract/Free Full Text]
  2. Basara ML, McCarthy JB, Barnes DW, and Furcht LT. Stimulation of haptotaxis and migration of tumor cells by serum spreading factor. Cancer Res 45: 2487–2494, 1985.[Abstract/Free Full Text]
  3. Basbaum CB and Werb Z. Focalized proteolysis: spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr Opin Cell Biol 8: 731–738, 1996.[CrossRef][ISI][Medline]
  4. Brooks PC, Clark RA, and Cheresh DA. Requirement of vascular integrin {alpha}vß3 for angiogenesis. Science 264: 569–571, 1994.[Abstract/Free Full Text]
  5. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, and Cheresh DA. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin {alpha}vß3. Cell 85: 683–693, 1996.[CrossRef][ISI][Medline]
  6. Chambers AF, Groom AC, and MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572, 2002.[CrossRef][ISI][Medline]
  7. Chrzanowska-Wodnicka M and Burridge K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol 133: 1403–1415, 1996.[Abstract/Free Full Text]
  8. Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, and Stracke ML. Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res 63: 5446–5453, 2003.[Abstract/Free Full Text]
  9. Davis GE. Affinity of integrins for damaged extracellular matrix: {alpha}vß3 binds to denatured collagen type I through RGD sites. Biochem Biophys Res Commun 182: 1025–1031, 1992.[CrossRef][ISI][Medline]
  10. Della Rocca GJ, Maudsley S, Daaka Y, Lefkowitz RJ, and Luttrell LM. Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade. Role of focal adhesions and receptor tyrosine kinases. J Biol Chem 274: 13978–13984, 1999.[Abstract/Free Full Text]
  11. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, and Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430: 1034–1039, 2004.[CrossRef][Medline]
  12. El-Badry OM, Minniti C, Kohn EC, Houghton PJ, Daughaday WH, and Helman LJ. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ 1: 325–331, 1990.[Abstract]
  13. Evers EE, Zondag GC, Malliri A, Price LS, ten Klooster JP, van der Kammen RA, and Collard JG. Rho family proteins in cell adhesion and cell migration. Eur J Cancer 36: 1269–1274, 2000.[CrossRef][ISI][Medline]
  14. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186, 1971.[ISI][Medline]
  15. Fotouhi N, Lugo A, Visnick M, Lusch L, Walsky R, Coffey JW, and Hanglow AC. Potent peptide inhibitors of stromelysin based on the prodomain region of matrix metalloproteinases. J Biol Chem 269: 30227–30231, 1994.[Abstract/Free Full Text]
  16. Friedl P and Brocker EB. The biology of cell locomotion within three-dimensional extracellular matrix. Cell Mol Life Sci 57: 41–64, 2000.[CrossRef][ISI][Medline]
  17. Friedl P, Noble PB, Walton PA, Laird DW, Chauvin PJ, Tabah RJ, Black M, and Zanker KS. Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res 55: 4557–4560, 1995.[Abstract/Free Full Text]
  18. Frisch SM and Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 9: 701–706, 1997.[CrossRef][ISI][Medline]
  19. Fukata Y, Amano M, and Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 22: 32–39, 2001.[CrossRef][Medline]
  20. Gherardi E and Stoker M. Hepatocyte growth factor—scatter factor: mitogen, motogen, and met. Cancer Cells 3: 227–232, 1991.[ISI][Medline]
  21. Giancotti FG and Ruoslahti E. Integrin signaling. Science 285: 1028–1032, 1999.[Abstract/Free Full Text]
  22. Guo W and Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5: 816–826, 2004.[CrossRef][ISI][Medline]
  23. Hall A. Rho GTPases and the actin cytoskeleton. Science 279: 509–514, 1998.[Abstract/Free Full Text]
  24. Henson JH, Svitkina TM, Burns AR, Hughes HE, MacPartland KJ, Nazarian R, and Borisy GG. Two components of actin-based retrograde flow in sea urchin coelomocytes. Mol Biol Cell 10: 4075–4090, 1999.[Abstract/Free Full Text]
  25. Ishii I, Fukushima N, Ye X, and Chun J. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 73: 321–354, 2004.[CrossRef][ISI][Medline]
  26. Juliano RL. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol 42: 283–323, 2002.[CrossRef][ISI][Medline]
  27. Kassis J, Lauffenburger DA, Turner T, and Wells A. Tumor invasion as dysregulated cell motility. Semin Cancer Biol 11: 105–117, 2001.[CrossRef][ISI][Medline]
  28. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, and Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273: 245–248, 1996.[Abstract]
  29. Klominek J, Robert KH, and Sundqvist KG. Chemotaxis and haptotaxis of human malignant mesothelioma cells: effects of fibronectin, laminin, type IV collagen, and an autocrine motility factor-like substance. Cancer Res 53: 4376–4382, 1993.[Abstract/Free Full Text]
  30. Lauffenburger DA and Horwitz AF. Cell migration: a physically integrated molecular process. Cell 84: 359–369, 1996.[CrossRef][ISI][Medline]
  31. Lee HY, Clair T, Mulvaney PT, Woodhouse EC, Aznavoorian S, Liotta LA, and Stracke ML. Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin. J Biol Chem 271: 24408–24412, 1996.[Abstract/Free Full Text]
  32. Liotta LA. Tumor invasion and metastases—role of the extracellular matrix: Rhoads Memorial Award Lecture. Cancer Res 46: 1–7, 1986.[Free Full Text]
  33. Liotta LA, Espina V, Mehta AI, Calvert V, Rosenblatt K, Geho D, Munson PJ, Young L, Wulfkuhle J, and Petricoin EF 3rd. Protein microarrays: meeting analytical challenges for clinical applications. Cancer Cell 3: 317–325, 2003.[CrossRef][ISI][Medline]
  34. Liotta LA, Kleinerman J, and Saidel GM. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34: 997–1004, 1974.[Abstract/Free Full Text]
  35. Liotta LA and Kohn EC. The microenvironment of the tumour-host interface. Nature 411: 375–379, 2001.[CrossRef][Medline]
  36. Liotta LA, Saidel MG, and Kleinerman J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 36: 889–894, 1976.[Abstract/Free Full Text]
  37. Liotta LA, Steeg PS, and Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991.[CrossRef][ISI][Medline]
  38. Lynch CC and Matrisian LM. Matrix metalloproteinases in tumor-host cell communication. Differentiation 70: 561–573, 2002.[CrossRef][ISI][Medline]
  39. McCarthy JB and Furcht LT. Laminin and fibronectin promote the haptotactic migration of B16 mouse melanoma cells in vitro. J Cell Biol 98: 1474–1480, 1984.[Abstract/Free Full Text]
  40. Melchiori A, Albini A, Ray JM, and Stetler-Stevenson WG. Inhibition of tumor cell invasion by a highly conserved peptide sequence from the matrix metalloproteinase enzyme prosegment. Cancer Res 52: 2353–2356, 1992.[Abstract/Free Full Text]
  41. Mills GB and Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3: 582–591, 2003.[CrossRef][ISI][Medline]
  42. Montgomery AM, Reisfeld RA, and Cheresh DA. Integrin {alpha}vß3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci USA 91: 8856–8860, 1994.[Abstract/Free Full Text]
  43. Moolenaar WH, van Meeteren LA, and Giepmans BN. The ins and outs of lysophosphatidic acid signaling. Bioessays 26: 870–881, 2004.[CrossRef][ISI][Medline]
  44. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, and Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56, 2001.[CrossRef][Medline]
  45. Murphy G and Gavrilovic J. Proteolysis and cell migration: creating a path? Curr Opin Cell Biol 11: 614–621, 1999.[CrossRef][ISI][Medline]
  46. Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, and Stracke ML. Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Cancer Res 61: 6938–6944, 2001.[Abstract/Free Full Text]
  47. Okamoto H, Takuwa N, Yokomizo T, Sugimoto N, Sakurada S, Shigematsu H, and Takuwa Y. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol Cell Biol 20: 9247–9261, 2000.[Abstract/Free Full Text]
  48. Ornstein DK, Gillespie JW, Paweletz CP, Duray PH, Herring J, Vocke CD, Topalian SL, Bostwick DG, Linehan WM, Petricoin EF 3rd, and Emmert-Buck MR. Proteomic analysis of laser capture microdissected human prostate cancer and in vitro prostate cell lines. Electrophoresis 21: 2235–2242, 2000.[CrossRef][ISI][Medline]
  49. Paweletz CP, Charboneau L, Bichsel VE, Simone NL, Chen T, Gillespie JW, Emmert-Buck MR, Roth MJ, Petricoin IE, and Liotta LA. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 20: 1981–1989, 2001.[CrossRef][ISI][Medline]
  50. Ray JM and Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J 7: 2062–2072, 1994.[Abstract]
  51. Ruiter DJ, van Krieken JH, van Muijen GN, and de Waal RM. Tumour metastasis: is tissue an issue? Lancet Oncol 2: 109–112, 2001.[Medline]
  52. Saba J. Lysophospholipids in development: miles apart and edging in. J Cell Biochem 92: 967–992, 2004.[CrossRef][Medline]
  53. Sheehan KM, Calvert VS, Kay EW, Liu Y, Fishman DS, Espina V, Aquino J, Speer R, Araujo R, Mills GB, Liotta LA, Petricoin EF, and Wulfkuhle JD. Use of reverse phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma. Mol Cell Proteomics 4: 346–355, 2005. First published January 25, 2005; doi:10.1074/mcp. T500003-MCP200.[Abstract/Free Full Text]
  54. Stetler-Stevenson WG, Krutzsch HC, Wacher MP, Margulies IM, and Liotta LA. The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. J Biol Chem 264: 1353–1356, 1989.[Abstract/Free Full Text]
  55. Stracke ML, Kohn EC, Aznavoorian SA, Wilson LL, Salomon D, Krutzsch HC, Liotta LA, and Schiffmann E. Insulin-like growth factors stimulate chemotaxis in human melanoma cells. Biochem Biophys Res Commun 153: 1076–1083, 1988.[CrossRef][ISI][Medline]
  56. Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, and Liotta LA. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267: 2524–2529, 1992.[Abstract/Free Full Text]
  57. Takuwa Y. Subtype-specific differential regulation of Rho family G proteins and cell migration by the Edg family sphingosine-1-phosphate receptors. Biochim Biophys Acta 1582: 112–120, 2002.[Medline]
  58. Talhouk RS, Bissell MJ, and Werb Z. Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol 118: 1271–1282, 1992.[Abstract/Free Full Text]
  59. Taraboletti G, Roberts DD, and Liotta LA. Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains. J Cell Biol 105: 2409–2415, 1987.[Abstract/Free Full Text]
  60. Tchao R. Novel forms of epithelial cell motility on collagen and on glass surfaces. Cell Motil 2: 333–341, 1982.[Medline]
  61. Tilly BC, Tertoolen LG, Remorie R, Ladoux A, Verlaan I, de Laat SW, and Moolenaar WH. Histamine as a growth factor and chemoattractant for human carcinoma and melanoma cells: action through Ca2+-mobilizing H1 receptors. J Cell Biol 110: 1211–1215, 1990.[Abstract/Free Full Text]
  62. Wang JM, Taraboletti G, Matsushima K, Van Damme J, and Mantovani A. Induction of haptotactic migration of melanoma cells by neutrophil activating protein/interleukin-8. Biochem Biophys Res Commun 169: 165–170, 1990.[CrossRef][ISI][Medline]
  63. Werb Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 91: 439–442, 1997.[CrossRef][ISI][Medline]
  64. Woodhouse EC, Chuaqui RF, and Liotta LA. General mechanisms of metastasis. Cancer 80: 1529–1537, 1997.[CrossRef][ISI][Medline]
  65. Woodside DG. Dancing with multiple partners. Sci STKE 2002: PE14, 2002.
  66. Wu DY and Goldberg DJ. Regulated tyrosine phosphorylation at the tips of growth cone filopodia. J Cell Biol 123: 653–664, 1993.[Abstract/Free Full Text]




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