Cancer and Metastasis Reviews 11: 1-3, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Overview
Molecular mechanisms of cell motility E.A. Turley
Cell locomotion is a poorly understood biological phenomena that is relevant to many physiological processes and diseases, in particular tumor progression [1]. It has been known for some time that many transformed cells do not display contact inhibition of locomotion [2] while more recently, studies have shown that highly metastatic cells locomote more rapidly than poorly metastatic cells [3-5]. Mohler and colleagues [5] further showed that the metastatic capacity of the tumor cells could be predicted from their motile behavior. However, the most predictive motile characteristic was the ability of the tumor cells to form pseudopods [6]. Interestingly, this ability is central to a response to chemoattractants. Indeed, a heightened ability of tumor cells to respond to chemoattractants may be critical to their dissemination during tumor progression and distinguish highly malignant cells from their more sedentary counterparts. Very recent studies also emphasize that translocation can occur passively due to the contraction of the surrounding extracellular matrix (see Guidry this issue) and that tumor cells release factors such as endothelins that effect this. Like cell locomotion in response to chemoattractants, the ability of cells to contract their environment requires ligand:receptor and signal transduction events. Our understanding of the molecular mechanisms regulating cell locomotion is rapidly evolving as is demonstrated by the reviews included in this issue. Major advances include the identification of regulatory molecules, signal transduction pathways and increasing numbers of cytoskeletal proteins that provide a contractile function. Significant advances in the area of cytoskeletal proteins has in the past been accomplished with organisms such as dictyostelium which are more amenable to manipulation
than mammalian cells. As discussed in reviews by Cunningham, Condeelis et al. and Wilson et al., this experimental paradigm is now being successfully applied to mammalian tumor cells. It is becoming clear that at least 3 components are required for tumor cell locomotion, particularly chemotaxis, to occur. These include ligand:receptor interactions that include adhesive functions, signal transduction with concommittent messenger activation and modification of the cytoskeleton. It is also likely that a multitude of gene products (ie. proteases) are involved in this process. A large number of 'ligands' have been identified as regulators of cell locomotion. These can be classified as three general groups that include extracellular matrix, motility factors and growth factors, Most are potent chemoattractants as well as being able to increase random translocation. The extracellular matrix molecules include collagen [7] fibronectin [8, 9] laminin [7, 10], elastin [11], and hyaluronan (Turley this issue) and can serve adhesive as well as signal transducing functions (see Lister and McCarthy this issue). Motility factors include scatter factor [12-14], autocrine motility factor (AMF; [15, 16] and see NaN et al. this issue), hepatoma derived tumor motility factor [17] and migration stimulation factor [18[. A variety of growth factors including TGFB~, PDGF, BjFGF, EGF and IGF [19] have been shown to promote locomotion. In this issue, the most recent developments on the role of autocrine motility factor (see NaN et al.), fibronectin/laminin (see Lester and McCarthy) and hyaluronan (see Turley) are presented. It is not clear as yet whether these factors act synergistically with one another or independently. For instance, one possible paradigm is that growth factors regulate the release of motility factors which in turn
regulate production of extracellular matrix and their receptors, with the latter ultimately impacting upon locomotion. Alternatively, each may act independantly to signal separate transduction pathways in a manner that collectively culminate in cell locomotion. The isolation and molecular characterization of receptors for many of the chemotactic ligands are in early stages. Some such as the integrins (see Lester and McCarthy), and several growth factor receptors have been well studied. Most however, remain to be characterized. In this issue, the recently cloned receptor for AMF (see Nabi et al.) is reviewed as is a novel hyaluronan receptor critical to transformed cell locomotion (see Turley). In some instances, ligand-receptor interactions effect primarily adhesive or detaching functions (see Lester and McCarthy), but it is becoming clear that many molecules that were perceived to function primarily via their physio-chemical properties also affect cell locomotion by signal transduction and activation of second messengers. Signal transduction following ligand binding and clustering of the receptors or adhesion molecules appears to require G protein involvement (see Condeelis et al. and Lester and McCarthy). The precise order of intracellular events that result in the first morphological response of cells to chemoattractants, visa vie pseudopod extension, has not been defined. However, it appears that calcium influx and activation of phospholipase C occur that result in the generation of innositol triphosphate (IP3) and diacyl-glycerol (DAG). Concommittently, a reduction in PIP2 occurs that normally sequesters actin severing and capping proteins (ie gelsolin, see Cunningham; profilin, Lester and McCarthy). These innitial events are acute and occur within seconds of ligand binding. The study of AMF regulation of signal transduction indicates that chronic signalling is important and I P 3 has been observed to be released in increased amounts several hours after stimulation. Study of hyaluronan regulated locomotion also implicates protein tyrosine phosphorylation and predicts that some signalling pathways may not involve G-proteins. It has been understood for a long time that the cytoskeleton is critical to cell locomotion. In this
issue the role of myosin and actin severing, capping bundling and crosslinking proteins as contractile forces are presented (see Cunningham, Condeelis et al., and Wilson et aI., this issue). All three papers propose exciting new models for force generation that differ from the classical actin-myosin sliding model of muscle contraction. It is the intent of this issue to bring together disparate areas documenting major advances in cell locomotion in the context of cancer research. In particular, areas of cell motility research were chosen in which exciting molecular advances have been made and/or models proposed that challenge accepted theories of cell locomotion. These reviews may contradict one another in the models that are proposed but they emphasize the complexity of this phenomena, its obvious relevance to cancer research and raise important questions for future research that underscores our relative ignornance of the molecular mechanisms governing this fascinating biological property.
References 1. Zetter BR: The cellular basis of site specific tumor metastasis. NEJM 322: 605-612, 1990 2. Abercrombie: The crawling movement of metazoan cells. Proc R Soc Lond (Biol) 207: 129-147, 1980 3. Hosaka S, Suzuki M, Goto M, Sato H: Motility of rat ascites hepatoma cells, with reference to malignant characteristics in cancer metastasis. Gann 69: 273-276, 1978 4. Raz A, Ben-Ze'ev A: Cell contact and architecture of malignant cells and their relationship to metastasis. Cancer Metastasis Rev 6: 3-21, 1987 5. Mohler JL, Partin AW, Coffey DS: Prediction of metastatic potential by a new grading system of cell motility:validation in the Dunning R-327 prostatic adenocarcinoma model. J Urol 138: 168-170, 1987 6. Partin NW, Isaacs JT, Trieger B, Coffey DS. Early cell motility changes associated with an increase in metastatic ability in rat prostatic cancer cells transfected with V-Harvey-ras oncogene. Cancer Res 48: 6050-6053, 1988 7. Aznavoorian SA, Stracke ML, Krutzsch H, Schiffman E, Liotta LA: Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumor cells. J Cell Biol 110: 1427-1438, 1990 8. McCarthy JB, Hager SJ, Furcht LTF: Human fibronectin contains distinct adhesion-and motility promoting domains for metastatic melanoma cells. J Cell Biol 102: 179-188, 1986
9. Mensing H, Albini A, Krieg T, Pontz BF, Muller PK: Enhanced chemotaxis of tumor-derived and virus-transformed cells to fibronectin and fibroblast conditioned medium. Int J Cancer 33: 43-48, 1985 10. McCarthy JB, Basara ML, Palm SL, Sas DF, Furcht LT: The role of cell adhesion proteins laminin and fibronectin in the movement of malignant and metastatic cells. Cancer Met Rev 4: 125-152, 1985 11. Yusa T, Blood CM, Zetter BR: Tumor cell interactions with elastin: implications for pulmonary metastasis. Am Rev Respir Dis 140: 1458-1462, 1989 12. Gherardi E, Gray M, Stoker M, Perryman M, Fulong R: Proc Natl Acad Sci USA 86: 5844-5848, 1989 13. Rosen EM, Meromsky L, Setter E, Vinter DW, Go[dberg ID: Quantitation of cytokine stimulated migration of endothelium and epithelium by a new assay using microcarrier beads. Exp Cell Res 186: 22-31, 1990 14. Stoker M, Gherardi E, Perryman M, Grey J: Scatter factor is a fibroblast derived modulator of epithelial cell mobility. Nature 327: 239-242, 1987
15. Atnip KD, Carter LM, Nicolson GL, Dabbous MK: Chemotactic response of rat mammary adenocarcinoma cell clones to tumor derived cytokines. Biochem Biophys Res Comm 146: 996-1002, 1987 16. Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang FPK, Schiffmann E. Tumor cell autocrine motility factor. Proc Natl Acad Sci USA 83: 3302-3306, 1986 17. Yoshida K, Ozaki T, Ushijina K, Hayashi H: Studies on the mechanisms of invasion in cancer. I. Isolation and purification of a factor chemotactic for cancer cells. Int J Cancer 6: 123--132, 1970 18. Schor SL, Schor AM, Grey AM, Rushton G: Foetal and cancer patient fibroblasts produce an autocrine migration stimulating factor not made by normal adult cells. J Cell Sci 90: 391-399, 1988 19. Stracke ML, Engel JD, Wilson LW, Rjechler MM, Liotta LA, Schiffman JE. The type 1 IGF receptor is a motility receptor in human melanoma cells. J Biol Chem 264: 21544-21549
Overview
Molecular mechanisms of cell motility E.A. Turley
Cell locomotion is a poorly understood biological phenomena that is relevant to many physiological processes and diseases, in particular tumor progression [1]. It has been known for some time that many transformed cells do not display contact inhibition of locomotion [2] while more recently, studies have shown that highly metastatic cells locomote more rapidly than poorly metastatic cells [3-5]. Mohler and colleagues [5] further showed that the metastatic capacity of the tumor cells could be predicted from their motile behavior. However, the most predictive motile characteristic was the ability of the tumor cells to form pseudopods [6]. Interestingly, this ability is central to a response to chemoattractants. Indeed, a heightened ability of tumor cells to respond to chemoattractants may be critical to their dissemination during tumor progression and distinguish highly malignant cells from their more sedentary counterparts. Very recent studies also emphasize that translocation can occur passively due to the contraction of the surrounding extracellular matrix (see Guidry this issue) and that tumor cells release factors such as endothelins that effect this. Like cell locomotion in response to chemoattractants, the ability of cells to contract their environment requires ligand:receptor and signal transduction events. Our understanding of the molecular mechanisms regulating cell locomotion is rapidly evolving as is demonstrated by the reviews included in this issue. Major advances include the identification of regulatory molecules, signal transduction pathways and increasing numbers of cytoskeletal proteins that provide a contractile function. Significant advances in the area of cytoskeletal proteins has in the past been accomplished with organisms such as dictyostelium which are more amenable to manipulation
than mammalian cells. As discussed in reviews by Cunningham, Condeelis et al. and Wilson et al., this experimental paradigm is now being successfully applied to mammalian tumor cells. It is becoming clear that at least 3 components are required for tumor cell locomotion, particularly chemotaxis, to occur. These include ligand:receptor interactions that include adhesive functions, signal transduction with concommittent messenger activation and modification of the cytoskeleton. It is also likely that a multitude of gene products (ie. proteases) are involved in this process. A large number of 'ligands' have been identified as regulators of cell locomotion. These can be classified as three general groups that include extracellular matrix, motility factors and growth factors, Most are potent chemoattractants as well as being able to increase random translocation. The extracellular matrix molecules include collagen [7] fibronectin [8, 9] laminin [7, 10], elastin [11], and hyaluronan (Turley this issue) and can serve adhesive as well as signal transducing functions (see Lister and McCarthy this issue). Motility factors include scatter factor [12-14], autocrine motility factor (AMF; [15, 16] and see NaN et al. this issue), hepatoma derived tumor motility factor [17] and migration stimulation factor [18[. A variety of growth factors including TGFB~, PDGF, BjFGF, EGF and IGF [19] have been shown to promote locomotion. In this issue, the most recent developments on the role of autocrine motility factor (see NaN et al.), fibronectin/laminin (see Lester and McCarthy) and hyaluronan (see Turley) are presented. It is not clear as yet whether these factors act synergistically with one another or independently. For instance, one possible paradigm is that growth factors regulate the release of motility factors which in turn
regulate production of extracellular matrix and their receptors, with the latter ultimately impacting upon locomotion. Alternatively, each may act independantly to signal separate transduction pathways in a manner that collectively culminate in cell locomotion. The isolation and molecular characterization of receptors for many of the chemotactic ligands are in early stages. Some such as the integrins (see Lester and McCarthy), and several growth factor receptors have been well studied. Most however, remain to be characterized. In this issue, the recently cloned receptor for AMF (see Nabi et al.) is reviewed as is a novel hyaluronan receptor critical to transformed cell locomotion (see Turley). In some instances, ligand-receptor interactions effect primarily adhesive or detaching functions (see Lester and McCarthy), but it is becoming clear that many molecules that were perceived to function primarily via their physio-chemical properties also affect cell locomotion by signal transduction and activation of second messengers. Signal transduction following ligand binding and clustering of the receptors or adhesion molecules appears to require G protein involvement (see Condeelis et al. and Lester and McCarthy). The precise order of intracellular events that result in the first morphological response of cells to chemoattractants, visa vie pseudopod extension, has not been defined. However, it appears that calcium influx and activation of phospholipase C occur that result in the generation of innositol triphosphate (IP3) and diacyl-glycerol (DAG). Concommittently, a reduction in PIP2 occurs that normally sequesters actin severing and capping proteins (ie gelsolin, see Cunningham; profilin, Lester and McCarthy). These innitial events are acute and occur within seconds of ligand binding. The study of AMF regulation of signal transduction indicates that chronic signalling is important and I P 3 has been observed to be released in increased amounts several hours after stimulation. Study of hyaluronan regulated locomotion also implicates protein tyrosine phosphorylation and predicts that some signalling pathways may not involve G-proteins. It has been understood for a long time that the cytoskeleton is critical to cell locomotion. In this
issue the role of myosin and actin severing, capping bundling and crosslinking proteins as contractile forces are presented (see Cunningham, Condeelis et al., and Wilson et aI., this issue). All three papers propose exciting new models for force generation that differ from the classical actin-myosin sliding model of muscle contraction. It is the intent of this issue to bring together disparate areas documenting major advances in cell locomotion in the context of cancer research. In particular, areas of cell motility research were chosen in which exciting molecular advances have been made and/or models proposed that challenge accepted theories of cell locomotion. These reviews may contradict one another in the models that are proposed but they emphasize the complexity of this phenomena, its obvious relevance to cancer research and raise important questions for future research that underscores our relative ignornance of the molecular mechanisms governing this fascinating biological property.
References 1. Zetter BR: The cellular basis of site specific tumor metastasis. NEJM 322: 605-612, 1990 2. Abercrombie: The crawling movement of metazoan cells. Proc R Soc Lond (Biol) 207: 129-147, 1980 3. Hosaka S, Suzuki M, Goto M, Sato H: Motility of rat ascites hepatoma cells, with reference to malignant characteristics in cancer metastasis. Gann 69: 273-276, 1978 4. Raz A, Ben-Ze'ev A: Cell contact and architecture of malignant cells and their relationship to metastasis. Cancer Metastasis Rev 6: 3-21, 1987 5. Mohler JL, Partin AW, Coffey DS: Prediction of metastatic potential by a new grading system of cell motility:validation in the Dunning R-327 prostatic adenocarcinoma model. J Urol 138: 168-170, 1987 6. Partin NW, Isaacs JT, Trieger B, Coffey DS. Early cell motility changes associated with an increase in metastatic ability in rat prostatic cancer cells transfected with V-Harvey-ras oncogene. Cancer Res 48: 6050-6053, 1988 7. Aznavoorian SA, Stracke ML, Krutzsch H, Schiffman E, Liotta LA: Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumor cells. J Cell Biol 110: 1427-1438, 1990 8. McCarthy JB, Hager SJ, Furcht LTF: Human fibronectin contains distinct adhesion-and motility promoting domains for metastatic melanoma cells. J Cell Biol 102: 179-188, 1986
9. Mensing H, Albini A, Krieg T, Pontz BF, Muller PK: Enhanced chemotaxis of tumor-derived and virus-transformed cells to fibronectin and fibroblast conditioned medium. Int J Cancer 33: 43-48, 1985 10. McCarthy JB, Basara ML, Palm SL, Sas DF, Furcht LT: The role of cell adhesion proteins laminin and fibronectin in the movement of malignant and metastatic cells. Cancer Met Rev 4: 125-152, 1985 11. Yusa T, Blood CM, Zetter BR: Tumor cell interactions with elastin: implications for pulmonary metastasis. Am Rev Respir Dis 140: 1458-1462, 1989 12. Gherardi E, Gray M, Stoker M, Perryman M, Fulong R: Proc Natl Acad Sci USA 86: 5844-5848, 1989 13. Rosen EM, Meromsky L, Setter E, Vinter DW, Go[dberg ID: Quantitation of cytokine stimulated migration of endothelium and epithelium by a new assay using microcarrier beads. Exp Cell Res 186: 22-31, 1990 14. Stoker M, Gherardi E, Perryman M, Grey J: Scatter factor is a fibroblast derived modulator of epithelial cell mobility. Nature 327: 239-242, 1987
15. Atnip KD, Carter LM, Nicolson GL, Dabbous MK: Chemotactic response of rat mammary adenocarcinoma cell clones to tumor derived cytokines. Biochem Biophys Res Comm 146: 996-1002, 1987 16. Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang FPK, Schiffmann E. Tumor cell autocrine motility factor. Proc Natl Acad Sci USA 83: 3302-3306, 1986 17. Yoshida K, Ozaki T, Ushijina K, Hayashi H: Studies on the mechanisms of invasion in cancer. I. Isolation and purification of a factor chemotactic for cancer cells. Int J Cancer 6: 123--132, 1970 18. Schor SL, Schor AM, Grey AM, Rushton G: Foetal and cancer patient fibroblasts produce an autocrine migration stimulating factor not made by normal adult cells. J Cell Sci 90: 391-399, 1988 19. Stracke ML, Engel JD, Wilson LW, Rjechler MM, Liotta LA, Schiffman JE. The type 1 IGF receptor is a motility receptor in human melanoma cells. J Biol Chem 264: 21544-21549
