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Extracellular Matrix: A Solid‐State Regulator of Cell form, Function, and Tissue Development

Donald E. Ingber

10.1002/cphy.cp140112

Source: Supplement 31: Handbook of Physiology, Cell Physiology

Originally published: 1997

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Extracellular Matrix: Composition and Structure
2 Extracellular Matrix and Tissue Architecture
3 Functions of the Extracellular Matrix
3.1 Physiological Cell Attachment Foundation
3.2 Spatial Organizer of Polarized Epithelium
3.3 Solid‐State Growth Regulator
3.4 Inducer of Differentiation
3.5 Tissue Boundary
3.6 Storage Site for Soluble Regulators
3.7 Scaffolding for Orderly Tissue Renewal and Repair
3.8 Target for Deregulation during Tumor Formation and Invasion
4 Transmembrane Signaling Across Matrix Receptors
4.1 Cell Surface Matrix Receptors
4.2 Chemical Signaling
4.3 Mechanical Signaling
4.4 Signal Integration
5 Conclusions
Figure 1. Figure 1.

Interstitial matrix versus basement membrane (BM). Phase contrast (A,C) and immunofluorescence (B,D) micrographs of frozen sections of normal rat exocrine pancreas stained with antibodies against interstitial type III collagen (A,B) or BM type IV collagen (C,D). Interstitial fibrillar collagen is distributed in an amorphous pattern filling the connective tissue space. Basement membrane collagen appears in a linear pattern (planar in three dimensions) and therefore forms a physical tissue boundary separating the epithelium and vascular endothelium from surrounding connective tissue.
Figure 2. Figure 2.

Extracellular matrix (ECM) and tissue development. Pattern formation during morphogenesis results from establishment of local differentials of cell growth, ECM turnover, the tissue expansion. Regions of tissue expansion correspond to areas in which basement membrane (BM) turnover and cell proliferation are the highest. Importantly, the rate of BM deposition must exceed its degradation in regions of rapid growth and turnover because net growth (lateral extension) of BM is observed during tissue development. Differences in tissue pattern (for example, glandular acini versus vascular tubes) result from differences in the number and distribution of the growth centers. Glandular morphogenesis involves complex epithelial‐mesenchymal interactions whereas angiogenesis (capillary morphogenesis) appears to be driven largely by the endothelial cell itself (see text for appropriate references).
Figure 3. Figure 3.

Extracellular matrix (ECM) and tissue remodeling. Changes in basement membrane (BM) turnover that accompany tissue growth and involution during capillary development are shown here. Regions of the growing vessel that undergo the most active remodeling exhibit high rates of ECM turnover. However, BM synthesis must exceed BM degradation to produce net BM extension in these regions. Formation of new stable tissue form correlates with a decrease in BM degradation and accumulation of an intact BM. Once fully formed, BM synthesis and degradation are maintained at very low and approximately equal levels throughout adult life. In contrast, growing tissues may be induced to regress by rapidly increasing ECM degradation or by inhibiting ECM deposition, such that total dissolution of BM results. Normal cells rapidly lose viability when they are freed from anchorage and thus progressive tissue involution ensues. During involution, cells at the leading edge that sit on the BM with the highest turnover rate are the first to lose their adhesions and retract. This proceeds backwards along the growing sprout in a progressive manner until the entire vessel involutes 59. In this sense, controlled tissue involution is essentially normal tissue development in reverse.
Figure 4. Figure 4.

Basement membranes (BM) supports cell attachment and spreading. Scanning electron micrograph showing that exogenous intact BM (isolated from human amnion) can promote cell attachment and spreading, even in the presence of the protein synthesis inhibitor cycloheximide (experimental details are described in ref. 62).
Figure 5. Figure 5.

Basement membrane (BM) and epithelial polarity. Top: Cells consistently orient within polarized epithelium, nucleus and rough endoplasmic reticulum (ER) at the base, Golgi complex above, and secretory granules in the apex, as shown in this electron micrograph of rat exocrine pancreas. Bottom: A higher magnification image from the same view showing that the highly polarized epithelium sits atop a continuous BM that separates the cells from the surrounding connective tissue space. Tips of the small arrows abut on the epithelial BM; L, lumen of a small capillary.
Figure 6. Figure 6.

Diagram of the focal adhesion complex. The extracellular portion of integrin receptors recognize specific amino acid binding sites (for example, RGD) within extracellular matrix (ECM) molecules. The intracellular portion of these receptors physically interlinks with the actin cytoskeleton via binding interactions with actinassociated proteins, such as talin, α‐actinin, vinculin, and paxillin. This localized membrane/cytoskeletal microdomain also has been found to contain molecules that are thought to mediate chemical signaling by ECM (for example, the protein kinases, c‐src and FAK kinase). The precise location of these proteins within the complex is currently unknown.
Figure 7. Figure 7.

Extracellular matrix (ECM) mechanics and control of cell function. Cells exert tension on their ECM adhesions. Highly adhesive ECM substrata that are malleable (for example, native collagen gels, Matrigel, thin silicone rubber) can not resist cytoskeletal tension and thus they promote cell rounding. However, if the same substrata are made rigid (for example, due to chemical crosslinking or immobilizing the gel on a dish), they support cell extension. Similar changes in cell shape can be induced by varying the ability of a rigid substratum to resist cell tension. This can be done by changing the density of a single type of purified ECM molecule (for example, fibronectin, laminin, or different collagen types) that is preadsorbed on otherwise nonadhesive dishes. For many cell types, round cells tend to maintain high levels of tissue‐specific functions, whereas spread cells turn off differentiation and switch on growth, regardless of the method of cell shape control (see text for appropriate references).


Figure 1.

Interstitial matrix versus basement membrane (BM). Phase contrast (A,C) and immunofluorescence (B,D) micrographs of frozen sections of normal rat exocrine pancreas stained with antibodies against interstitial type III collagen (A,B) or BM type IV collagen (C,D). Interstitial fibrillar collagen is distributed in an amorphous pattern filling the connective tissue space. Basement membrane collagen appears in a linear pattern (planar in three dimensions) and therefore forms a physical tissue boundary separating the epithelium and vascular endothelium from surrounding connective tissue.



Figure 2.

Extracellular matrix (ECM) and tissue development. Pattern formation during morphogenesis results from establishment of local differentials of cell growth, ECM turnover, the tissue expansion. Regions of tissue expansion correspond to areas in which basement membrane (BM) turnover and cell proliferation are the highest. Importantly, the rate of BM deposition must exceed its degradation in regions of rapid growth and turnover because net growth (lateral extension) of BM is observed during tissue development. Differences in tissue pattern (for example, glandular acini versus vascular tubes) result from differences in the number and distribution of the growth centers. Glandular morphogenesis involves complex epithelial‐mesenchymal interactions whereas angiogenesis (capillary morphogenesis) appears to be driven largely by the endothelial cell itself (see text for appropriate references).



Figure 3.

Extracellular matrix (ECM) and tissue remodeling. Changes in basement membrane (BM) turnover that accompany tissue growth and involution during capillary development are shown here. Regions of the growing vessel that undergo the most active remodeling exhibit high rates of ECM turnover. However, BM synthesis must exceed BM degradation to produce net BM extension in these regions. Formation of new stable tissue form correlates with a decrease in BM degradation and accumulation of an intact BM. Once fully formed, BM synthesis and degradation are maintained at very low and approximately equal levels throughout adult life. In contrast, growing tissues may be induced to regress by rapidly increasing ECM degradation or by inhibiting ECM deposition, such that total dissolution of BM results. Normal cells rapidly lose viability when they are freed from anchorage and thus progressive tissue involution ensues. During involution, cells at the leading edge that sit on the BM with the highest turnover rate are the first to lose their adhesions and retract. This proceeds backwards along the growing sprout in a progressive manner until the entire vessel involutes 59. In this sense, controlled tissue involution is essentially normal tissue development in reverse.



Figure 4.

Basement membranes (BM) supports cell attachment and spreading. Scanning electron micrograph showing that exogenous intact BM (isolated from human amnion) can promote cell attachment and spreading, even in the presence of the protein synthesis inhibitor cycloheximide (experimental details are described in ref. 62).



Figure 5.

Basement membrane (BM) and epithelial polarity. Top: Cells consistently orient within polarized epithelium, nucleus and rough endoplasmic reticulum (ER) at the base, Golgi complex above, and secretory granules in the apex, as shown in this electron micrograph of rat exocrine pancreas. Bottom: A higher magnification image from the same view showing that the highly polarized epithelium sits atop a continuous BM that separates the cells from the surrounding connective tissue space. Tips of the small arrows abut on the epithelial BM; L, lumen of a small capillary.



Figure 6.

Diagram of the focal adhesion complex. The extracellular portion of integrin receptors recognize specific amino acid binding sites (for example, RGD) within extracellular matrix (ECM) molecules. The intracellular portion of these receptors physically interlinks with the actin cytoskeleton via binding interactions with actinassociated proteins, such as talin, α‐actinin, vinculin, and paxillin. This localized membrane/cytoskeletal microdomain also has been found to contain molecules that are thought to mediate chemical signaling by ECM (for example, the protein kinases, c‐src and FAK kinase). The precise location of these proteins within the complex is currently unknown.



Figure 7.

Extracellular matrix (ECM) mechanics and control of cell function. Cells exert tension on their ECM adhesions. Highly adhesive ECM substrata that are malleable (for example, native collagen gels, Matrigel, thin silicone rubber) can not resist cytoskeletal tension and thus they promote cell rounding. However, if the same substrata are made rigid (for example, due to chemical crosslinking or immobilizing the gel on a dish), they support cell extension. Similar changes in cell shape can be induced by varying the ability of a rigid substratum to resist cell tension. This can be done by changing the density of a single type of purified ECM molecule (for example, fibronectin, laminin, or different collagen types) that is preadsorbed on otherwise nonadhesive dishes. For many cell types, round cells tend to maintain high levels of tissue‐specific functions, whereas spread cells turn off differentiation and switch on growth, regardless of the method of cell shape control (see text for appropriate references).

References
 1. Adams, J. C, and F. M. Watt. Fibronectin inhibits terminal differentiation of human keratinocytes. Nature 340: 307–309, 1989.
 2. Adams, J. C, and F. M. Watt. Changes in keratinocyte adhesion during terminal differentiation: reduction in fibronectin binding precedes α5β1 integrin loss from the cell surface. Cell 63: 425–435, 1990.
 3. Albelda, A. M., and C. A. Buck. Integrins and other cell adhesion molecules. FASEB J. 4: 2868–2880, 1990.
 4. Albrecht‐Buehler, G. In defense of “nonmolecular” cell biology. Int. Rev. Cytol. 120: 191–241, 1990.
 5. Anderson, M. J., and D. M. Fambrough. Aggregates of acetylcholine receptors are associated with plaques of basal lamina heparan sulfate proteoglycan on the surface of skeletal muscle fibers. J. Cell Biol. 97: 396–1411, 1983.
 6. Axelrod, D., P. Raudin, D. E. Koppel, J. Schlessinger, W. W. Webb, E. L. Elson, and T. R. Podleski. Lateral motion of fluorescently labeled acetylcholine receptors in membranes of developing muscle fibers. Proc. Natl. Acad. Sci. U.S.A. 73: 4594–4598, 1976.
 7. Aznavoorian, S., M. L. Stracke, H. Krutzsch, E. Schiffman, and L. A. Liotta. Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumor cells. J. Cell Biol. 110: 1427–1438, 1990.
 8. Banerjee, S. D., R. H. Cohn, and M. R. Bernfield. Basal lamina of embryonic salivary epithelia. Production by the epithelium and role in maintaining lobular morphology. J. Cell Biol. 73: 445–463, 1977.
 9. Banga, H. S., E. R. Simons, L. F. Brass, and S. E. Rittenhouse. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. Proc. Natl. Acad. Sci. U.S.A. 83: 9197–9201, 1986.
 10. Ben Ze'ev, A., S. R. Farmer, and S. Penman. Protein synthesis requires cell‐surface contact while nuclear events respond to cell shape in anchorage‐dependent fibroblasts. Cell 21: 365–372, 1980.
 11. Ben Ze'ev, A. G., S. Robinson, N. L. Bucher, and S. R. Farmer. Cell‐cell and cell‐matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 85: 1–6, 1988.
 12. Bernfield, M. R., and S. D. Benerjee. The basal lamina in epithelial‐mesenchymal interactions. In: Biology and Chemistry of Basement Membranes, edited by N. Kefalides, New York: Academic Press, 1978, p. 137–148.
 13. Bernfield, M. R., S. D. Banerjee, and R. H. Cohn. Dependence of salivary epithelial morphology and branching morphogenesis upon acid mucopolysaccharide‐protein proteoglycan at the epithelial cell surface. J. Cell Biol. 52: 674–689, 1972.
 14. Bernfield, M. R., R. Kokenyesi, M. Kato, M. T. Hinkes, J. Spring, R. L. Gallo, and E. J. Lose. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 8: 365–393, 1992.
 15. Bissell, M. G., H. G. Hall, and G. Parry. How does extracellular matrix direct gene expression? J. Theor. Biol. 99: 31–68, 1982.
 16. Breuer, D., and C. Wagener. Activation of the phosphatidylinositol cycle in spreading cells. Exp. Cell Res. 182: 659–663, 1989.
 17. Brown, S. S., H. L. Malinoff, and M. S. Wicha. Connectin: cell surface protein that binds both laminin and actin. Proc. Natl. Acad. Sci. U.S.A. 80: 5927–5930, 1983.
 18. Burden, S. J., P. B. Sargent, and U. J. McMahan. Acetylcholine receptors accumulate at original synaptic sites in the absence of nerve. J. Cell Biol. 82: 412–425, 1979.
 19. Burridge, K. Substrate adhesion in normal and transformed fibroblasts: organization and regulation of cytoskeletal, membrane, and extracellular matrix components at focal contacts. Cancer Rev. 4: 18–78, 1986.
 20. Buxbaum, R. E., and S. R. Heidemann. A thermodynamic model for force integration and microtubule assembly during axonal elongation. J. Theor. Biol. 134: 379–390, 1988.
 21. Carter, W. G., P. Kauer, S. G. Gil, P. J. Gahr, and E. A. Wayner. Distinct functions for integrins α3β1 in focal adhesions and α6β4/bullous pemphigoid antigen in a new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes. J. Cell Biol. 111: 3141–3154, 1990.
 22. Charo, I. F., L. Nannizzi, J. W. Smith, and D. A. Cheresh. The vitronectin receptor αvβ3 binds fibronectin and acts in concert with α5β1 in promoting cellular attachment and spreading on fibronectin. J. Cell Biol. 111: 2795–2800, 1990.
 23. Clark, P., P. Connolly, A.S.G. Curtis, J.A.T. Dow, and C.D.W. Wilkinson. Topographical control of cell behaviour: II. Multiple grooved substrata. Development 108: 635–644, 1990.
 24. Cybulsky, A. V., J. V. Bonventre, R. F. Quigg, L. S. Wolfe, and D. J. Salant. Extracellular matrix regulates proliferation and phospholipid turnover in glomerular epithelial cells. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F326–F337, 1990.
 25. Danowski, B. Fibroblast contractility and actin organization are stimulated by microtubule inhibitors. J. Cell Sci. 93: 255–266, 1989.
 26. David, G., and M. R. Bernfield. Collagen reduces glycosaminoglycan degradation by cultured mammary epithelial cells: possible mechanism for basal lamina formation. Proc. Natl. Acad. Sci. U.S.A. 76: 786–790, 1979.
 27. Davis, S., M. L. Lu, S. H. Lo, S. Lin, J. A Butler, B. J. Drucker, T. M. Roberts, Q. An, and L. B. Chen. Presence of an SH2 domain in the actin‐binding protein tensin. Science 252: 712–715, 1991.
 28. Dike, L., and S. Farmer. Cell adhesion induces expression of growth associated genes in suspension‐arrested fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 85: 5792–6796, 1988.
 29. Dodson, J. W., and E. D. Hay. Control of corneal differentiation by extracellular materials. Collagen as promotor and stabilizer of epithelial stroma production. Dev. Biol. 38: 249–270, 1971.
 30. Ekblom, P., K. Alitalo, A. Vaheri, R. Timpl, and L. Saxen. Induction of a basement membrane glycoprotein in embryonic kidney: possible role of laminin in morphogenesis. Proc. Natl. Acad. Sci. U.S.A. 77: 485–489, 1980.
 31. Emerman, J. T., and D. R. Pitelka. Maintenance and induction of morphological differentiation in dissociated mammary epithelium on floating collagen membranes. In Vitro 13: 316–328, 1977.
 32. Farquhar, M. G., Structure and function in glomerular capillaries: role of the basement membrane in glomerular filtration. In: Biology and Chemistry of Basement Membranes, edited by N. Kefalides, New York: Academic Press, 1978, p. 137–148.
 33. Felder, S., and E. L. Elson. Mechanics of fibroblast locomotion: quantitative analysis of forces and motions at the leading lamella of fibroblasts. J. Cell Biol. 6: 2415–2526, 1990.
 34. Ferrell, Jr. J. R., and G. S. Martin. Tyrosine‐specific protein phosphorylation is regulated by glycoprotein Ilb/IIIa in platelets. Proc. Natl. Acad. Sci. U.S.A. 86: 2234–2238, 1989.
 35. Folkman, J. Angiogenesis: initiation and control. Ann. N.Y. Acad. Sci. 401: 212–227, 1982.
 36. Folkman, J., M. K. Klagsbrun, J. Sasse, M. Wadzinski, D. E. Ingber, and I. Vlodavsky. A heparin‐binding angiogenic protein—basic fibroblast growth factor—is stored within basement membrane. Am. J. Pathol. 130: 393–400, 1988.
 37. Folkman, J., and A. Moscona. Role of cell shape in growth control. Nature 273: 345–349, 1978.
 38. Frazier, W. A. Thrombospondins. Curr. Opin. Cell Biol. 3: 792–799, 1991.
 39. Gallick, S., S. Usami, K. M. Jan, and S. Chien. Shear stress‐induced detachment of human polymorphonuclear leukocytes from endothelial cell monolayers. Biorheology 26: 823–834, 1989.
 40. Goldschmidt‐Clermont, P. J., L. M. Machesky, J. J. Baldassare, and T. D. Pollard. The actin‐binding protein profilin binds to PIP2 and inhibits its hydrolysis by phospholipase C. Science 247: 1575–1578, 1990.
 41. Gordon, M. K., and B. R. Olsen. The contribution of collagenous proteins to tissue‐specific matrix assemblies. Curr. Opin. Cell Biol. 2: 833–838, 1990.
 42. Guadagno, T. M., and R. K. Assoian. G1/S control of anchorage‐independent growth in the fibroblast cell cycle. J. Cell Biol. 115: 1419–1425, 1991.
 43. Hansen, L. K., and D. E. Ingber. Regulation of nucleocytoplasmic transport by mechanical forces transmitted through the cytoskeleton. In: Nuclear Trafficking, edited by C. Feldherr, San Diego: Academic Press, 1992, p. 71–86.
 44. Harris, G. K., D. Stopak, and P. Wild. Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290: 249–251, 1981.
 45. Heidemann, S. R., and R. E. Buxbaum. Tension as a regulator and integrator of axonal growth. Cell Motil. Cytoskeleton 17: 6–10, 1990.
 46. Horvath, A., and S. Kellie. Regulation of integrin motility and cytoskeletal association in normal and RSV‐transformed chick embryo fibroblasts. J. Cell Sci. 97: 307–315, 1990.
 47. Hubbard, B. B., M. W. Glacken, J. R. Rodgers, and R. R. Rich. The role of physical forces on cytotoxic T cell‐target cell conjugate stability. J Immunol 144: 4129–4138, 1990.
 48. Hynes, R. O. Integrin signaling. Cell 69: 11–25, 1992.
 49. Ikawa, H., R. L. Trelstad, J. M. Hutson, T. F. Manganara, and P. K. Donahoe. Changing patterns of fibronectin, laminin, type IV collagen, and a basement membrane proteoglycan during rat Mullerian duct regression. Dev. Biol. 102: 260–263, 1984.
 50. Ingber, D. E. Integrins as mechanochemical transducers. Curr. Opin. Cell Biol. 3: 841–848, 1991.
 51. Ingber, D. E. Fibronectin controls capillary endothelial cell growth by modulating cell shape. Proc. Natl. Acad. Sci. U.S.A. 87: 3579–3583, 1990.
 52. Ingber, D. E. Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J. Cell Sci. 104: 613–627, 1993.
 53. Ingber, D. E., and J. Folkman. Inhibition of angiogenesis through inhibition of collagen metabolism. Lab. Invest. 59: 44–51, 1988.
 54. Ingber, D. E., and J. Folkman. How does extracellular matrix control capillary morphogenesis? Cell 58: 803–805, 1989.
 55. Ingber, D. E., and J. Folkman. Mechanochemical switching between growth and differentiation during fibroblast growth factor‐stimulated angiogenesis in vitro: role of extracellular matrix. J. Cell Biol. 109: 317–330, 1989.
 56. Ingber, D. E., and J. Folkman. Tension and compression as basic determinants of cell form and function: utilization of a cellular tensegrity mechanism. In: Cell Shape: Determinants, Regulation and Regulatory Role, edited by W. Stein and F. Bronner, Orlando: Academic Press, 1989, p. 1–32.
 57. Ingber, D. E., and J. D. Jamieson. Cells as tensegrity structures: architectural regulation of histodifferentiation by physical forces tranduced over basement membrane. In: Gene Expression During Normal and Malignant Differentiation, edited by L. C. Andersson, C. G. Gahmberg, and P. Ekblom, Orlando: Academic Press, 1985, p. 13–32.
 58. Ingber, D. E., S. Karp, G. Plopper, L. Hansen, and D. Mooney. Mechanochemical transduction across extracellular matrix and through the cytoskeleton. In: Physical Forces and the Mammalian Cell, edited by J. A. Frangos and C. L. Ives, San Diego: Academic Press, 1993, p. 61–79.
 59. Ingber, D. E., J. A. Madri, and J. Folkman. A possible mechanism for inhibition of angiogenesis by angiostatic steroids: induction of capillary basement membrane dissolution. Endocrinology 119: 1768–1775, 1986.
 60. Ingber, D. E., J. A. Madri, and J. Folkman. Extracellular matrix regulates endothelial growth factor action through modulation of cell and nuclear expansion. In Vitro Cell Dev. Biol. 23: 387–394, 1987.
 61. Ingber, D. E., J. A. Madri, and J. D. Jamieson. Neoplastic disorganization of pancreatic epithelial cell‐cell relations: role of basement membrane. Am. J. Pathol. 121: 248–260, 1985.
 62. Ingber, D. E., J. A. Madri, and J. D. Jamieson. Basement membrane as a spatial organizer of polarized epithelia: exogenous basement membrane reorients pancreatic epithelial tumor cells in vitro. Am. J. Pathol. 122: 129, 1986.
 63. Ingber, D. E., D. Prusty, J. Frangione, E. J. Cragoe, Jr., C. Lechene, and M. A. Schwartz. Control of intracellular pH and growth by fibronectin in capillary endothelial cells. J. Cell Biol. 110: 1803–1812, 1990.
 64. Jaconi, M. E., J. M. Theler, W. Schlegel, R. D. Appel, S. D. Wright, and P. D. Lew. Multiple elevations of cytosolic‐free Ca2+ in human neutrophils: initiation by adherence receptors of the integrin family. J. Cell Biol. 112: 1249–1257, 1991.
 65. Janmey, P. A., and T. P. Stossel. Modulation of gelsolin functions by phosphatidylinositol 4,5‐biphosphate. Nature 325: 362–364, 1987.
 66. Kenyon, K., S. Contente, P. C. Trackman, J. Tang, H. M. Kagan, and R. M. Friedman. Lysyl oxidase and rrg messenger RNA. Science 253: 802, 1991.
 67. Khokha, R., and D. T. Denhardt. Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion and Metastasis 9: 391–405, 1989.
 68. Klebe, R. J., H. Caldwell, and S. Milam. Cells transmit spatial information by orienting collagen fibers. Matrix 9: 451–458, 1989.
 69. Kleinman, H. K., R. J. Klebe, and G. R. Martin. Role of collagenous matrices in the adhesion and growth of cells. J. Cell Biol. 88: 473–485, 1981.
 70. Koch, J. The laws of bone architecture. Am. J. Anat. 21: 177–298, 1917.
 71. Kolodney, M. S., and R. B. Wyslomerski. Isometric contraction by fibroblasts and endothelial cells: a quantitative study. J. Cell Biol. 117: 73–82, 1992.
 72. Kubota, Y., H. K. Kleinman, G. R. Martin, and T. J. Lawley. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary‐like structures. J. Cell Biol. 107: 1589–1598, 1988.
 73. Lampugnani, M. G., M. Giorgi, E. Dejana, and P. C. Marchisio. Endothelial cell motility, integrin receptor clustering, and microfilament organization are inhibited by agents that increase intracellular cAMP. Lab. Invest. 63 (4): 521–531, 1990.
 74. Leivo, I. Structure and composition of early basement membranes: studies with early embryos and teratocarcinoma cells. Med. Biol. 61: 1–30, 1983.
 75. Leivo, I., A. Vaheri, R. Timpl, and J. Wartiovaara. Appearance and distribution of collagens and laminin in the early mouse embryo. Dev. Biol. 76: 1000–1114, 1980.
 76. Letsou, G. V., O. Rosales, S. Maitz, A. Vogt, and B. E. Sumpio. Stimulation of adenylate cyclase activity in cultured endothelial cells subjected to cyclic stretch. J. Cardiovasc. Surg. 31: 634–639, 1990.
 77. Li, M. L., J. Aggeler, D. A. Farson, C. Hatier, J. Hassell, and M. J. Bissell. Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 84: 136–140, 1987.
 78. Liotta, L. A., P. S. Steeg, and W. G. Stetler‐Stevenson. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991.
 79. Liotta, L. A., K. Tryggvason, S. Garbisa, I. Hart, C. M. Foltz, and S. Shafie. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284: 67–68, 1980.
 80. Lotz, M. M., C. A. Burdal, H. P. Erickson, and D. R. McClay. Cell adhesion to fibronectin and tenascin: quantitative measurements of initial binding and subsequent strengthening strenghtening response. J. Cell Biol. 109: 1795–1805, 1989.
 81. Lynch, S. E., J. C. Nixon, R. B. Colvin, and H. N. Antoniades. The role of platelet‐derived growth factor in wound healing: synergistic effects with other growth factors. Proc. Natl. Acad. Sci. U.S.A. 84: 7696–7700, 1987.
 82. Madri, J. A., and K. S. Stenn. Aortic endothelial cell migration: I. Matrix requirements and composition. Am. J. Pathol. 106: 180–186, 1982.
 83. Maragoudakis, M. E., M. Sarmonika, and M. Panoutsacopoulou. Inhibition of basement membrane biosynthesis prevents angiogenesis. J. Pharm. Exp. Ther. 244: 729–733, 1988.
 84. McNamee, H., H. G. Liley, and D. E. Ingber. Integrin‐dependent control of inositol lipid synthesis in vascular endothelial cells and smooth muscle cells. Exp. Cell Res. 224: 116–122, 1996.
 85. McNamee, H., D. E. Ingber, and M. A. Schwartz. Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF‐induced inositol lipid breakdown. J. Cell Biol. 121: 673–678, 1993.
 86. Mercurio, A. M. Laminins: multiple forms, multiple receptors. Curr. Opin. Cell Biol. 2: 845–849, 1990.
 87. Mochitate, K., P. Pawelek, and F. Grinnell. Stress relaxation of contracted collagen gels: Disruption of actin filament bundles, release of cell surface fibronectin, and down‐regulation of DNA and protein synthesis. Exp. Cell Res. 193: 198–207, 1991.
 88. Mooney, D., L. Hansen, S. Farmer, J. Vacanti, R. Langer, and D. Ingber. Switching from differentiation to growth in hepatocytes: control by extracellular matrix. J. Cell Physiol. 151: 497–505, 1992.
 89. Mooney, D., R. Langer, L. K. Hansen, J. P. Vacanti, and D. E. Ingber. Induction of hepatocyte differentiation by the extracellular matrix and an RGD‐containing synthetic peptide. Proc. Mat. Res. Soc. Symp. Proc. 252: 199–204, 1992.
 90. Moses, M. A., and R. Langer. A metalloproteinase inhibitor as an inhibitor of neovascularization. J. Cell. Biochem. 47: 230–235, 1991.
 91. Mosher, D. F., J. Suttile, C. Wu, and J. A. McDonald. Assembly of extracellular matrix. Curr. Opin. Cell Biol. 4: 810–818, 1992.
 92. Nogawa, H., and Y. Nakanishi. Mechanical aspects of the mesenchymal influence on epithelial branching morphogenesis of mouse salivary gland. Development 101: 491–500, 1987.
 93. O'Neill, C., P. Jordan, and P. Riddle. Narrow linear strips of adhesive substratum are powerful inducers of both growth and total focal contact area. J. Cell Sci. 95: 577–586, 1990.
 94. Opas, M. Expression of the differentiated phenotype by epithelial cells in vitro is regulated by both biochemistry and mechanics of the substratum. Dev. Biol. 131: 281–293, 1989.
 95. Plopper, G., H. P. McNamee, L. E. Dike, K. Bojanowski, and D. E. Ingber. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol. Biol. Cell 6: 1349–1365, 1995.
 96. Pollanen, J., O. Saksela, E. M. Salonen, P. Andreasen, L. Nielsen, K. Dano, and A. Vaheri. Distinct localizations of urokinase‐type plasminogen activator and its type 1 inhibitor under cultured human fibroblasts and sarcoma cells. J. Cell Biol. 104: 1085–1096, 1987.
 97. Rasenick, M. M., N. Wang, and K. Yan. Specific associations between tubulin and G proteins: participation of cytoskeletal elements in cellular signal transduction. Biol. Med. Signal Trans. 381–386, 1990.
 98. Rastinejad, F., P. F. Polverini, and N. P. Bouck. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 56: 345–355, 1989.
 99. Reid, L. M. Stem cell biology, hormone/matrix synergies and liver differentiation. Curr. Opin. Cell Biol. 2: 121–130, 1990.
 100. Rodriguez‐Boulan, E., and W. J. Nelson. Morphogenesis of the polarized epithelial cell phenotype. Science 245: 718–725, 1989.
 101. Rodriguez‐Boulan, E., K. T. Paskiet, and D. D. Sabatini. Assembly of enveloped viruses in Madin‐Darby canine kidney cells: polarized budding from single attached cell and from clusters of cells in suspension. J. Cell Biol. 96: 866–874, 1983.
 102. Sachs, F. Mechanical transduction in biological systems. Crit. Rev. Biomed. Eng. 16: 141–169, 1988.
 103. Sakakura, T., Y. Nishizura, and C. Dawe. Mesenchyme‐dependent morphogenesis and epithelium‐specific cytodifferentiation in mouse mammary gland. Science 194: 1439–1441, 1976.
 104. Sanes, J. R., E. Engvall, R. Butowski, and D. Hunter. Molecular heterogeneity of basal laminae: isoforms of laminin and collagen IV at the neuromuscular junction and elsewhere. J. Cell Biol. 111: 1685–1699, 1990.
 105. Sanes, J. R., and J. C. Lawrence, Jr.. Activity‐dependent accumulation of basal lamina by cultured rat myotubules. Dev. Biol. 97: 123–136, 1983.
 106. Saunders, S., M. Jalkanen, S. O'Farrell, and M. R. Bernfield. Molecular cloning of syndecan, an integral membrane proteoglycan. J. Cell Biol. 108: 1547–1056, 1989.
 107. Schiro, J. A., B. M. Chan, W. T. Roswit, P. D. Kassner, A. P. Pentland, M. E. Hemler, A. Z. Eisen, and T. S. Kupper. Integrin α2β1 (VLA 2) mediates reorganization and contraction of collagen matrices by human cells. Cell 61: 403–401, 1991.
 108. Schittny, J. C., and P. Yurchenco. Basement membranes: molecular organization and function in development and disease. Curr. Opin. Cell Biol. 1: 983–988, 1989.
 109. Schmidhauser, C., M. J. Bissell, C. A. Myers, and G. F. Casperson. Extracellular matrix and hormones transcriptionally regulate bovine beta‐casein 5' sequences in stably transfected mouse mammary cells. Proc. Natl. Acad. Sci. U.S.A. 87: 9118–9122, 1990.
 110. Schwartz, M. A. Transmembrane signaling by integrins. Trends Cell Biol. 2: 304–308, 1992.
 111. Schwartz, M. A., D. E. Ingber, M. Laurence, T. A. Springer, and C. Lechene. Multiple integrins share the ability to induce elevation of intracellular pH. Exp. Cell Res. 195: 533–535, 1991.
 112. Schwartz, M. A., C. Lechene, and D. E. Ingber. Insoluble fibronectin activates the Na+ H+ antiporter by inducing clustering and immobilization of its receptor, independent of cell shape. Proc. Natl. Acad. Sci. U.S.A. 88: 7849–7853, 1991.
 113. Schwartzbauer, J. E. Fibronectin: from gene to protein. Curr. Opin. Cell Biol. 3: 786–791, 1991.
 114. Seyedin, S. M., and D. M. Rosen. Matrix proteins of the skeleton. Curr. Opin. Cell Biol. 2: 914–919, 1990.
 115. Shaw, L. M., J. M. Messier, and A. M. Mercurio. The activation dependent adhesion of macrophages to laminin involves cytoskeletal anchoring and phosphorylation of the α6β1 integrin. J. Cell Biol. 110: 2167–2174, 1990.
 116. Shin, S., V. H. Freedman, R. Risser, and R. Pollack. Tumorigenicity of virus‐transformed cells in nude mice is correlated specifically with anchorage‐independent growth in vitro. Proc. Natl. Acad. Sci. U.S.A. 72: 4435–4439, 1975.
 117. Sims, J., S. Karp, and D. E. Ingber. Altering the cellular mechanical force balance results in integrated changes in cell, cytoskeletal, and nuclear shape. J. Cell Sci. 103: 1215–1222, 1992.
 118. Singhvi, R., A. Kumar, G. P. Lopez, G. N. Stephanopoulos, D. I. C. Wang, G. M. Whitesides, and D. E. Ingber. Engineering cell shape and function. Science 264: 696–698, 1994.
 119. Smith, J. C., J. P. Singh, J. S. Lillquist, D. S. Goon, and C. D. Stiles. Growth factors adherent to cell substrate are mitogenically active in situ. Nature 296: 154–156, 1982.
 120. Smith, R. L., and M. R. Bernfield. Mesenchyme cells degrade epithelial basal lamina glycosaminoglycan. Dev. Biol. 94: 378–390, 1982.
 121. Sorokin, L., A. Sonnenberg, M. Aumailley, R. Timpl, and P. Ekblom. Recognition of the laminin E8 cell‐binding site by an integrin possessing the α6 subunit is essential for epithelial polarization in developing kidney tubules. J. Cell Biol. 111: 1265–1273, 1990.
 122. Springer, T. A. The sensation and regulation of interactions with the extracellular environment: the cell biology of lymphocyte adhesion receptors. Annu. Rev. Cell Biol. 6: 359–402, 1990.
 123. Stenn, K. S., J. A. Madri, and F. J. Roll. Migrating epidermis produces AB2 collagen and requires continual collagen synthesis for movement. Nature 277: 229–232, 1979.
 124. Stoker, A. W., C. H. Streuli, M. Martins‐Green, and M. J. Bissell. Designer microenvironments for the analysis of cell and tissue function. Curr. Opin. Cell Biol. 2: 864–874, 1990.
 125. Streuli, C. H., and M. J. Bissell. Expression of extracellular matrix components is regulated by substratum. J. Cell Biol. 110: 1405–1415, 1990.
 126. Sugrue, S. P., and E. D. Hay. Response of basal epithelial cell surface and cytoskeleton to solubilized extracellular matrix molecules. J. Cell Biol. 91: 45–54, 1981.
 127. Talhouk, R. S., M. J. Bissell, and Z. Werb. Coordinate expression of extracellular matrix‐degrading proteinases and their inhibitors regulate mammary epithelial function during involution. J. Cell Biol. 118: 1271–1282, 1992.
 128. Toole, B. P. Hyaluronan and its binding proteins, the hyaladherins. Curr. Opin. Cell Biol. 2: 839–844, 1990.
 129. Truskey, G. A., and J. S. Pirone. The effect of fluid shear stress upon cell adhesion to fibronectin‐treated surfaces. J. Biomed. Mater. Res. 24: 1333–1353, 1990.
 130. Turner, C. E., and K. Burridge. Transmembrane molecular assemblies in cell‐extracellular matrix interactions. Curr. Opin. Cell Biol. 849–853, 1991.
 131. Vembu, D., L. A. Liotta, M. Paranjpe, and C. W. Boone. Correlation of tumorigenicity with resistance to growth inhibition by cis‐hydroxyproline. Exp. Cell Res. 124: 247–252, 1979.
 132. Vernon, R. B., J. C. Angello, L. Iruela‐Arispe, T. F. Lane, and E. H. Sage. Reorganization of basement membrane matrices by cellular traction promotes the formation of cellular networks in vitro. Lab. Invest. 66: 536–547, 1992.
 133. Vogel, Z., C. N. Christian, M. Vigny, H. C. Bauer, P. Sonderegger, and M. P. Daniels. Laminin induces acetylcholine receptor aggregation on cultured myotubes and enhances the receptor aggregation activity of a neuronal factor. J. Neurosci. 3: 1058–1068, 1983.
 134. Volk, T., L. I. Fessier, and J. H. Fessier. A role for integrin in the formation of sarcomeric cytoarchitecture. Cell 63: 525–536, 1990.
 135. Vracko, R. Basal lamina scaffold‐anatomy and significance for maintenance of orderly tissue structures. Am. J. Pathol. 77: 314–346, 1974.
 136. Wagner, V., C. Brian, and R. S. Quatrano. Role of a vitronectin‐like molecule in embryo adhesion of the brown alga Fucus. Proc. Natl. Acad. Sci. U.S.A. 89: 3644–3648, 1992.
 137. Wang, N., J. P. Butler, and D. E. Ingber. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260: 1124–1127, 1993.
 138. Watson, P. Direct stimulation of adenylate cyclase by mechanical forces in S49 mouse lymphoma cells during hyposomotic swelling. J. Biol. Chem. 265: 6569–6675, 1990.
 139. Wayne, R., M. P. Staves, and A. C. Leopold. The contribution of the extracellular matrix to gravisensing in characean cells. J. Cell Sci. 101: 611–623, 1992.
 140. Wayner, E. A., R. A. Orlando, and D. A. Cheresh. Integrins αvβ3 and αvβ5 contribute to cell attachment to vitronectrin but differentially distribute on the cell surface. J. Cell Biol. 113: 919–929, 1991.
 141. Welch, M. P., G. F. Odland, and R. F. Clark. Temporal relationships of F‐actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J. Cell Biol. 110: 133–145, 1990.
 142. Werb, Z., P. M. Tremble, O. Behrendtsen, E. Crowley, and C. H. Damsky. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J. Cell Biol. 109: 877–889, 1989.
 143. Wessells, N. K. Tissue Interactions and Development. New York: Benjamin Press, 1977.
 144. Wicha, M. S., L. A. Liotta, G. Garbisa, and W. R. Kidwell. Basement membrane collagen requirements for attachment and growth of mammary epithelium. Exp. Cell Res. 124: 181–190, 1979.
 145. Wicha, M. S., L. A. Liotta, B. K. Vonderhaar, and W. R. Kidwell. Effects of inhibition of basement membrane collagen deposition on rat mammary gland development. Dev. Biol. 80: 253–261, 1980.
 146. Willigen, G. V., and Akkerman, J. N. Protein kinase C and cyclic AMP regulate reversible exposure of binding sites for fibrinogen on the glycoprotein IIB—IIIA complex of human platelets. Biochem. J. 273: 115–120, 1991.
 147. Wirtz, H.R.W., and L. G. Dobbs. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 250: 1266–1269, 1990.
 148. Wittelsberger, S. C., K. Kleene, and S. Penman. Progressive loss of shape‐responsive metabolic controls in cells with increasingly transformed phenotype. Cell 24: 859–866, 1981.
 149. Yayon, A., M. Klagsbrun, J. D. Esko, P. Leder, and D. M. Ornitz. Cell surface heparin‐like molecules are required for binding of basic fibroblast growth factor to its high affinity receptors. Cell 64: 841–848, 1991.
 150. Zachary, I., and E. Rozengurt. Focal adhesion kinase (p125fak): a point of convergence in the action of neuropeptides, integrins, and on cogenes. Cell 71: 891–894, 1992.
 151. Zetter, B. R. The cellular basis of site‐specific tumor metastasis. N. Engl. J. Med. 322: 605–612, 1990.
 152. Zetter, B. R., and S. E. Brightman. Cell motility and the extracellular matrix. Curr. Opin. Cell Biol. 2: 850–56, 1990.

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Article Title: Extracellular Matrix: A Solid‐State Regulator of Cell form, Function, and Tissue Development
 

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Donald E. Ingber. Extracellular Matrix: A Solid‐State Regulator of Cell form, Function, and Tissue Development. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 541-556. First published in print 1997. doi: 10.1002/cphy.cp140112