Abstract
Epithelial-mesenchymal interactions areresponsible for the unique pattern of ductal branchingmorphogenesis characteristic of the mammary gland. Toinvestigate the factors which control the elongation and branching of lactiferous ducts, wedeveloped an in vitro model of ductal morphogenesis inwhich clonal mouse mammary epithelial cells (TAC-2cells) are grown in collagen gels. In this experimentalsystem, fibroblast conditioned medium (CM)3stimulates the formation of extensively arborizedtubules. The molecule responsible for this tubulogeniceffect was identified as hepatocyte growthfactor/scatter factor (HGF/SF). To determine whether HGF/SF plays arole in mammary gland morphogenesis in vivo, theexpression of HGF/SF and its receptor, cMet, wereanalyzed in the rat mammary gland during pregnancy,lactation, and involution. Levels of HGF/SF and c-Mettranscripts were progressively reduced during pregnancy,were virtually undetectable during lactation, andincreased again during involution. Collectively, these in vitro and in vivo findings suggest thatHGF/SF is a paracrine mediator of mammary gland ductalmorphogenesis. We subsequently investigated the effectof another multifunctional cytokine, namely TGF-beta1, on branching morphogenesis of TAC-2 cells.TGF-β1 had a striking biphasic effect:whereas relatively high concentrations of this cytokineinhibited colony formation, lower concentrationsstimulated extensive elongation and branching of epithelial cords.Taken together, these studies indicate that HGF/SF is astromal-derived paracrine mediator of mammary ductalmorphogenesis, and that when present at lowconcentrations, TGF-β1 can contribute to thisprocess.
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References
C. W. Daniel and G. B. Silberstein. (1987). Postnatal development of the rodent mammary gland. In M. C. Neville and C. W. Daniel (eds.), The Mammary Gland. Development, Regulation and Function Plenum Press, New York and London, pp. 3-36.
F. Borellini and T. Oka (1989). Growth control and differentiation in mammary epithelial cells. Environ. Health Perspect. 80: 85-99.
T. Sakakura (1991). New aspects of stroma-parenchyma relations in mammary gland differentiation. Int. Rev. Cytol. 125: 165-202.
S. Z. Haslam (1991). Stromal-epithelial interactions in normal and neoplastic mammary gland. In M. Lippman and R. Dickson (eds.), Regulatory Mechanisms in Breast Cancer Kluwer Academic Publishers, Boston, pp. 401-420.
G. R. Cunha and Y. K. Hom (1996). Role of mesenchymal-epithelial interactions in mammary gland development. J. Mam. Gland Biol. Neoplasia 1: 21-35.
T. Woodward, J. Xie, and S. Z. Haslam (1998). The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J. Mam. Gland Biol. Neoplasia 3: 117-132.
Y. J. Topper and S. Freeman (1980). Multiple hormone interactions in the developmental biology of the mammary gland. Physiol. Rev. 60: 1049-1106.
W. Imagawa, G. K. Bandyopadhyay, and S. Nandi (1990). Regulation of mammary epithelial cell growth in mice and rats. Endocrine Rev. 11: 494-523.
K. Kratochwil (1969). Organ specificity in mesenchymal induction demonstrated in the embryonic development of the mammary gland in the mouse. Devel. Biol. 20: 46-71.
M. H. Barcellos-Hoff, J. Aggeler, and M. J. Bissell (1989). Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development 105: 223-235.
C. H. Streuli and M. J. Bissell (1990). Expression of extracellular matrix components is regulated by substratum. J. Cell Biol. 110: 1405-1415.
J. Aggeler, J. Ward, L. M. Blackie, M. H. Barcellos Hoff, C. H. Streuli, and M. J. Bissell (1991). Cytodifferentiation of mouse mammary epithelial cells cultured on a reconstituted basement membrane reveals striking similarities to development in vivo. J. Cell Sci. 99: 407-417.
M. C. Neville, L. Stahl, A. Brozo, and J. Lowe-Lieber (1991). Morphogenesis and secretory activity of mouse mammary cultures on EHS biomatrix. Protoplasma 163: 1-8.
C. H. Streuli, N. Bailey, and M. J. Bissell (1991). Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J. Cell Biol. 115: 1383-1395.
J. Yang, J. Richards, R. Guzman, W. Imagawa, and S. Nandi (1980). Sustained growth in primary culture of normal mammary epithelial cells embedded in collagen gels. Proc. Natl. Acad. Sci. U.S.A. 77: 2088-2092.
D. C. Bennett (1980). Morphogenesis of branching tubules in cultures of cloned mammary epithelial cells. Nature 285: 657-659.
E. J. Ormerod and P. S. Rudland (1982). Mammary gland morphogenesis in vitro: formation of branched tubules in collagen gels by a cloned rat mammary cell line. Devel. Biol. 91: 360-375.
K. G. Danielson, C. J. Oborn, E. M. Durban, J. S. Butel, and D. Medina (1984). Epithelial mammary cell line exhibiting normal morphogenesis in vivo and functional differentiation in vitro. Proc. Natl. Acad. Sci. U.S.A. 81: 3756-3760.
I. Fialka, H. Schwarz, E. Reichmann, M. Oft, M. Busslinger, and H. Beug (1996). The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions. J. Cell Biol. 132: 1115-1132.
J. Enami, S. Enami, and M. Koga (1983). Growth of normal and neoplasic mouse mammary epithelial cells in primary culture: stimulation by conditioned medium from mouse mammary fibroblasts. Gann 74: 845-853.
T. Kanazawa and H. L. Hosick (1992). Transformed growth phenotype of mouse mammary epithelium in primary culture induced by specific fetal mesenchymes. J. Cell. Physiol. 153: 381-391.
R. B. Owens, H. S. Smith, and A. J. Hackett (1974). Epithelial cell cultures from normal glandular tissue of mice. J. Natl. Cancer Inst. 53: 261-269.
G. H. Hall, D. A. Farson, and M. J. Bissell (1982). Lumen formation by epithelial cell lines in response to collagen overlay: A morphogenetic model in culture. Proc. Natl. Acad. Sci. U.S.A. 79: 4672-4676.
G. David, B. Van der Schueren, and M. Bernfield (1981). Basal lamina formation by normal and transformed mouse mammary epithelial cells duplicated in vitro. J. Natl. Cancer Inst. 67: 719-724.
J. V. Soriano, M. S. Pepper, T. Nakamura, L. Orci, and R. Montesano (1995). Hepatocyte growth factor stimulates extensive development of branching duct-like structures by cloned mammary gland epithelial cells. J. Cell Sci. 108: 413-430.
E. Gherardi, J. Gray, M. Stoker, M. Perryman, and R. A Furlong (1989). Purification of scatter factor, a fibroblast-derived basic protein that modulates epithelial interactions and movement. Proc. Natl. Acad. Sci. U.S.A. 86: 5844-5848.
J. S. Rubin, A. M. Chan, D. P. Bottaro, W. H. Burgess, W. G. Taylor, A. C. Cech, D. W. Hirschfield, J. Wong, T. Miki, P. W. Finch, and S. A. Aaronson (1991). A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc. Natl. Acad. Sci. U.S.A. 88: 415-419.
R. Zarnegar and G. K. Michalopoulos (1995). The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J. Cell Biol. 129: 1177-1180.
E. M. Rosen, S. K. Nigam, and I. D. Goldberg (1994). Scatter factor and the c-Met receptor: a paradigm for mesenchymal/epithelial interaction. J Cell Biol. 127: 1783-1787.
K. Matsumoto and T. Nakamura (1996). Emerging multipotent aspects of hepatocyte growth factor. J. Biochem. (Tokyo) 119: 591-600.
L. Tamagnone and P. M. Comoglio (1997). Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors. Cytokine Growth Factor Rev. 8: 129-142.
R. Montesano, G. Schaller, and L. Orci (1991). Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors. Cell 66: 697-711.
R. Montesano, K. Matsumoto, T. Nakamura, and L. Orci (1991). Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 67: 901-908.
D. P. Bottaro, J. S. Rubin, D. L. Faletto, A. M. Chan, T. E. Kmiecik, G. F. Vande Woude, and S. A. Aaronson (1991). Identification of the hepatocyte growth factor receptor as the c-Met proto-oncogene product. Science 251: 802-804.
L. Naldini, E. Vigna, R. P. Narsimhan, G. Gaudino, R. Zarnegar, G. K. Michalopoulos, and P. M. Comoglio (1991). Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. Oncogene 6: 501-504.
K. M. Weidner, M. Sachs, and W. Birchmeier (1993). The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J. Cell Biol. 121: 145-154.
H. Zhu, M. A. Naujokas, E. D. Fixman, K. Torossian, and M. Park (1994). Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis. J. Biol. Chem. 269: 29943-29948.
I. Royal, T. M. Fournier, and M. Park. (1997). Differential requirement of Grb2 and PI3-kinase in HGF/SF-induced cell motility and tubulogenesis. J. Cell. Physiol. 173: 196-201.
K. M. Weidner, S. Di Cesare, M. Sachs, V. Brinkmann, J. Behrens, and W. Birchmeier (1996). Interaction between Gab1 and the c-Met tyrosine kinase is responsible for epithelial morphogenesis. Nature 384: 173-176.
K. S. Zettl, M. D. Sjaastad, P. M. Riskin, G. Parry, T. E. Machen, and G. L. Firestone (1992). Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc. Natl. Acad. Sci. U.S.A. 89: 9069-9073.
M. D. Sjaastad, K. S. Zettl, G. Parry, G. L. Firestone, and T. E. Machen (1993). Hormonal regulation of the polarized function and distribution of Na/H exchange and Na/HCO3 cotransport in cultured mammary epithelial cells. J. Cell Biol. 122: 589-600.
A. A. Donjacour and G. R. Cunha (1990). Stromal regulation of epithelial function. In M. Lippman and R. Dickson (eds.), Regulatory Mechanisms in Breast Cancer Kluwer Academic Publishers, Boston, pp. 335-364.
F. Berdichevsky, D. Alford, B. D'Souza, and J. Taylor-Papadimitriou (1994). Branching morphogenesis of human mammary epithelial cells in collagen gels. J. Cell Sci. 107: 3557-3568.
B. Niranjan, L. Buluwela, J. Yant, A. Atherton, D. Phippard, B. A. Gusterson, and T. Kamalati (1995). HGF/SF: a potent cytokine for mammary growth, morphogenesis and development. Development 121: 2897-2908.
Y. Yang, E. Spitzer, D. Meyer, M. Sachs, C. Niemann, G. Hartmann, K. M. Weidner, C. Birchmeier, and W. Birchmeier (1995). Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J. Cell Biol. 131: 215-226.
E. U. Saelman, P. J. Keely, and S. A. Santoro (1995). Loss of MDCK cell alpha 2 beta 1 integrin expression results in reduced cyst formation, failure of hepatocyte growth factor/scatter factor-induced branching morphogenesis, and increased apoptosis. J. Cell Sci. 108: 3531-3540.
A. L. Pollack, A. I. M. Barth, Y. Altschuler, W. J. Nelson, and K. E. Mostov (1997). Dynamics of β-catenin interactions with APC protein regulate epithelial tubulogenesis. J. Cell Biol. 137: 1651-1662.
M. S. Pepper, K. Matsumoto, T. Nakamura, L. Orci, and R. Montesano (1992). Hepatocyte growth factor increases urokinase-type plasminogen activator (u-PA) and u-PA receptor expression in Madin-Darby canine kidney epithelial cells. J. Biol. Chem. 267: 20493-20496.
S. E. Dunsmore, J. S. Rubin, S. O. Kovacs, M. Chedid, W. C. Parks, and H. G. Welgus (1996). Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. J. Biol. Chem. 271: 24576-24582.
M. Jeffers, S. Rong, and G. F. Vande Woude (1996). Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signaling in human cells concomitant with induction of the urokinase proteolysis network. Mol. Cell. Biol. 16: 1115-1125.
M. E. Zeigler, N. T. Dutcheshen, D. F. Gibbs, and J. Varani (1996). Growth factor-induced epidermal invasion of the dermis in human skin organ culture: expression and role of matrix metalloproteinases. Invasion Metastasis 16: 11-18.
M. S. Pepper, J. V. Soriano, P. A. Menoud, A. P. Sappino, L. Orci, and R. Montesano (1995). Modulation of hepatocyte growth factor and c-Met in the rat mammary gland during pregnancy, lactation, and involution. Exp. Cell Res. 219: 204-210.
L. Ossowski, D. Biegel, and E. Reich (1979). Mammary plasminogen activator: correlation with involution, hormonal modulation and comparison between normal and neoplastic tissue. Cell 16: 929-940.
C. J. Sympson, R. S. Talhouk, C. M. Alexander, J. R. Chin, S. M. Clift, M. J. Bissell, and Z. Werb (1994). Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J. Cell Biol. 125: 681-693.
M. Peaker (1978). Ion and water transport in the mammary gland. In B. L. Larson (ed.) Lactation. A Comprehensive Treatise. Volume IV, Academic Press, Inc., New York and London, pp. 437-462.
A. Nusrat, C. A. Parkos, A. E. Bacarra, P. J. Godowski, C. Delp Archer, E. M. Rosen, and J. L. Madara (1994). Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-Met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J. Clin. Invest. 93: 2056-2065.
A. B. Tuck, M. Park, E. E. Sterns, A. Boag, and B. E. Elliot (1996). Coexpression of hepatocyte growth factor and receptor (met) in human breast carcinoma. Am. J. Pathol. 148: 225-232.
L. Jin, A. Fuchs, S. J. Schnitt, Y. Yao, J. Ansamma, K. Lamszus, M. Park, I. D. Goldberg, and E. M. Rosen (1997). Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer 79: 749-760.
Y. Wang, A. C. Selden, N. Morgan, G. W. Stamp, and H. J. Hodgson (1994). Hepatocyte growth factor/scatter factor expression in human mammary epithelium. Am. J. Pathol. 144: 675-682.
N. Rahimi, E. Tremblay, L. McAdam, M. Park, R. Schwall, and B. Elliott (1996). Identification of a hepatocyte growth factor autocrine loop in a murine mammary carcinoma. Cell Growth Differ. 7: 263-270.
H. Takayama, W. J. LaRochelle, R. Sharp, T. Otsuka, P. Kriebel, M. Anver, S. A. Aaronson, and G. Merlino (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc. Natl. Acad. Sci. U.S.A. 94: 701-706.
T. J. Liang, A. E. Reid, R. Xavier, R. D. Cardiff, and T. C. Wang (1996). Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors. J. Clin. Invest. 97: 2872-2877.
Y. Yao, L. Jin, A. Fuchs, A. Joseph, H. M. Hastings, I. D. Goldberg, and E. M. Rosen (1996). Scatter factor protein levels in human breast cancers: clinicopathologi cal and biological correlations. Am. J. Pathol. 149: 1707-1717.
J. Nagy, G. W. Curry, K. J. Hillan, I. C. McKay, E. Mallon, A. D. Purushotham, and W. D. George (1996). Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer. Surg. Oncol. 5: 15-21.
J. Yamashita, M. Ogawa, S. Yamashita, K. Nomura, M. Kuramoto, T. Saishoji, and S. Shin (1994). Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res. 54: 1630-1633.
J. A. Barnard, R. M. Lyons, and H. L. Moses (1990). The cell biology of transforming growth factor-β. Biochim. Biophys. Acta 1032: 79-87.
J. Massagué (1990). The transforming growth factor-βfamily. Ann. Rev. Cell Biol. 6: 597-641.
A. B. Roberts and M. B. Sporn (1990). The transforming growth factor-βs. In M. B. Sporn and A. B. Roberts (eds.), Peptide Growth Factors and Their Receptors (Vol. I), Springer-Verlag, Berlin, pp. 419-472.
L. Attisano, J. L. Wrana, F. Lopez Casillas, and J. Massagué (1994). TGF-βreceptors and actions. Biochim. Biophys. Acta 1222: 71-80.
J. Massagué and K. Polyak (1995). Mammalian antiproliferative signals and their targets. Curr.Opin. Genet. Devel. 5: 91-96.
D. A. Lawrence (1996). Transforming growth factor-β: a general review. Eur. Cytokine Netw. 7: 363-374.
J. Plouet and D. Gospodarowicz (1989). Transforming growth factor-β1, positively modulates the bioactivity of fibroblast growth factor on corneal endothelial cells. J. Cell. Physiol. 141: 392-399.
E. J. Battegay, E. W. Raines, R. A. Seifert, D. F. Bowen Pope, and R. Ross (1990). TGF-βinduces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 63: 515-524.
Y. Myoken, M. Kan, G. H. Sato, W. L. McKeehan, and J. D. Sato (1990). Bifunctional effects of transforming growth factor-β (TGF-β) on endothelial cell growth correlate with phenotypes of TGF-βbinding sites. Exp. Cell Res. 191: 299-304.
M. S. Pepper, J. D. Vassalli, L. Orci, and R. Montesano (1993). Biphasic effect of transforming growth factor-β1 on in vitro angiogenesis. Exp. Cell Res. 204: 356-363.
P. J. Miettinen, R. Ebner, A. R. Lopez, and R. Derynck (1994). TGF-βinduced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127: 2021-2036.
C. Nathan and M. Sporn (1991). Cytokines in context. J. Cell Biol. 113: 981-986.
Z. Feng, A. Marti, B. Jehn, H. J. Altermatt, G. Chicaiza, and R. Jaggi (1995). Glucocorticoid and progesterone inhibit involution and progammed cell death in the mouse mammary gland. J. Cell Biol. 131: 1095-1103.
G. R. Merlo, F. Basolo, L. Fiore, L. Duboc, and N. E. Hynes (1995). p53-dependent and p53-independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin. J. Cell Biol. 128: 1185-1196.
J. V. Soriano, L. Orci, and R. Montesano (1996). TGF-β1 induces morphogenesis of branching cords by cloned mammary epithelial cells at subpicomolar concentrations. Biochem. Biophys. Res. Commun. 220: 879-885.
J. A. Madri, B. M. Pratt, and A. M. Tucker (1988). Phenotypic modulation of endothelial cells by transforming growth factor-βdepends upon the composition and organization of the extracellular matrix. J. Cell Biol. 106: 1375-1384.
R. Montesano and L. Orci (1988). Transforming growth factor β stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc. Natl. Acad. Sci. U.S.A. 85: 4894-4897.
S. Rasmussen and A. Rapraeger (1988). Altered structure of the hybrid cell surface proteoglycan of mammary epithelial cells in response to transforming growth factor-β. J. Cell Biol. 107: 1959-1967.
M. Hosobuchi and M. R. Stampfer (1989). Effects of transforming growth factor-β on growth of human mammary epithelial cells in culture. In Vitro Cell. Devel. Biol. 25: 705-713.
K. Takahashi, K. Suzuki, and T. Ono (1990). Loss of growth inhibitory activity of TGF-β toward normal human mammary epithelial cells grown within collagen gel matrix. Biochem. Biophys. Res. Commun. 173: 1239-1247.
P. Martikainen, N. Kyprianou, and J. T. Isaacs (1990). Effect of transforming growth factor-β1 on proliferation and death of rat prostatic cells. Endocrinology 127: 2963-2968.
S. D. Robinson, G. B. Silberstein, A. B. Roberts, K. C. Flanders, and C. W. Daniel (1991). Regulated expression and growth inhibitory effects of transforming growth factor-β isoforms in mouse mammary gland development. Development 113: 867-878.
G. B. Silberstein, K. C. Flanders, A. B. Roberts, and C. W. Daniel (1992). Regulation of mammary morphogenesis: evidence for extracellular matrix-mediated inhibition of ductal budding by transforming growth factor-β1. Devel. Biol. 152: 354-362.
G. B. Silberstein and C.W. Daniel (1987). Reversible inhibition of mammary gland growth by transforming growth factor-β. Science 237: 291-293.
C. W. Daniel, G. B. Silberstein, K. Van Horn, P. Strickland, and S. Robinson (1989). TGF-β1-induced inhibition of mouse mammary ductal growth: developmental specificity and characterization. Devel. Biol. 135: 20-30.
D. F. Pierce, Jr., M. D. Johnson, Y. Matsui, S. D. Robinson, L. I. Gold, A. F. Purchio, C. W. Daniel, B. L. M. Hogan, and H. L. Moses (1993). Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-β1. Genes Devel. 7: 2308-2317.
C. Jhappan, A. G. Geiser, E. C. Kordon, D. Bagheri, L. Hennighausen, A. B. Roberts, G. H. Smith, and G. Merlino (1993). Targeting expression of a transforming growth factor-β1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J. 12: 1835-1845.
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Soriano, J.V., Pepper, M.S., Orci, L. et al. Roles of Hepatocyte Growth Factor/Scatter Factor and Transforming Growth Factor-β1 in Mammary Gland Ductal Morphogenesis. J Mammary Gland Biol Neoplasia 3, 133–150 (1998). https://doi.org/10.1023/A:1018790705727
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DOI: https://doi.org/10.1023/A:1018790705727