Biomedical Research Education & Training
Faculty Member

Moses, Harold L., M.D.
Interim Chair, Department of Cancer Biology
Professor of Cancer Biology
Professor of Pathology, Microbiology and Immunology
Professor of Medicine
Hortense B. Ingram Chair in Cancer Research

Lab Url: N/A

Phone Number: 615-936-1374

Email Address: Hal.Moses@vanderbilt.edu

Moses, Harold's picture
Academic history
, Cumberland College, Williamsburg, KY
B.A., Berea College, Berea, KY
M.D., Vanderbilt University, Nashville, TN
, Nat'l. Inst. Health, NIAMD, Bethesda, MD

Office Address   Mailing Address

694 Preston Research Building

691 PRB 6838


Research Keywords
TGF, TGF?, Tumor suppressor genes, Cancer,Cancer Genetics,Genomics,Malignancy,Mouse,Mutation,Receptor,Si gnal transduction,Cancer,Genomics,Malignancy,Mouse,Receptor, Signal transduction,Transformation,Cancer,Genomics,Knockout,Malignancy,Mouse,Recombination,Signal transduction,Transformation

Research Specialty
Regulation of cell proliferation by growth factors, oncogenes, growth inhibitors and tumor suppressor genes.

Research Description
Accumulating data indicate that the stroma can play a critical role in cancer initiation and progression. TGF-beta signaling in both epithelial and stromal cells appears to be a key regulator of the stromal microenvironment. There is now compelling evidence from transgenic mouse studies and analyses of mutations in human carcinomas indicating that the TGF-beta signal transduction pathway is tumor suppressive. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-beta signal transduction, including DPC4/Smad4, Smad2, and the type I and type II TGF-beta receptor (T?RI and T?RII, respectively). However, there is some evidence that TGF-beta signaling can promote tumor progression in the later stages. In order to examine the roles of TGF-beta signaling in cancer more closely, we have generated mice with loxP sites flanking exon 2 of the type II receptor gene, Tgfbr2, and crossed them with mice expressing Cre driven by different epithelial specific promoters. Loss of TGF-beta signaling in six different epithelial cells gave a minimal phenotype. However, when challenged with oncogene expression or tumor suppressor gene impairment, there was rapid development of invasive and metastatic carcinomas supporting the hypothesis that epithelial cell autonomous TGF-beta signaling is tumor suppressive in both early and late stages of carcinogenesis. One mechanism appears to be enhanced expression of chemokines by Tgfbr2 null carcinoma cells with resultant recruitment of bone marrow derived cells that express abundant TGF-beta and MMPs in the tumor microenvironment and promote invasion and metastasis.

In contrast to the epithelial cell knockouts that gave a minimal phenotype, knockout of Tgfbr2 in stromal fibroblasts gave a striking epithelial phenotype in the mammary gland, prostate and forestomach, including epithelial pre-neoplasia and invasive carcinomas. One mechanism identified was paracrine stimulation of carcinoma cells by HGF, MSP and TGF-alpha. Another mechanism appeared to be over expression of chemokines by the knockout fibroblasts with recruitment of bone marrow derived cells. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues. The data indicate that TGF-beta signaling is a major regulator of chemokine secretion and resultant bone marrow cell infiltration and that targeting pathways that inhibit bone marrow cell differentiation or chemokine receptors may be useful in both therapy and prevention of cancer.


Publications
Bierie, B, Chung, CH, Parker, JS, Stover, DG, Cheng, N, Chytil, A, Aakre, M, Shyr, Y, Moses, HL. Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest, 119(6), 1571-82, 2009 PMCID:2689133

Bierie, B, Stover, DG, Abel, TW, Chytil, A, Gorska, AE, Aakre, M, Forrester, E, Yang, L, Wagner, KU, Moses, HL. Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res, 68(6), 1809-19, 2008

Yang, L, Huang, J, Ren, X, Gorska, AE, Chytil, A, Aakre, M, Carbone, DP, Matrisian, LM, Richmond, A, Lin, PC, Moses, HL. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell, 13(1), 23-35, 2008 PMCID:2245859

Cheng, N, Chytil, A, Shyr, Y, Joly, A, Moses, HL. Enhanced Hepatocyte Growth Factor Signaling by Type II Transforming Growth Factor-{beta} Receptor Knockout Fibroblasts Promotes Mammary Tumorigenesis. Cancer Res, 2007

Bierie, B, Moses, HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 6(7), 506-20, 2006

Ijichi, H, Chytil, A, Gorska, AE, Aakre, ME, Fujitani, Y, Fujitani, S, Wright, CV, Moses, HL. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev, 20(22), 3147-60, 2006 PMCID:1635149

Bierie, B, Moses, HL. Under pressure: stromal fibroblasts change their ways. Cell, 123(6), 985-7, 2005

Bierie, B, Moses, HL. TGF-beta and cancer. Cytokine Growth Factor Rev, 17(1-2), 29-40, 2005

Cheng, N, Bhowmick, NA, Chytil, A, Gorksa, AE, Brown, KA, Muraoka, R, Arteaga, CL, Neilson, EG, Hayward, SW, Moses, HL. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene, 24(32), 5053-68, 2005

Forrester, E, Chytil, A, Bierie, B, Aakre, M, Gorska, AE, Sharif-Afshar, AR, Muller, WJ, Moses, HL. Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res, 65(6), 2296-302, 2005

Bhowmick, NA, Neilson, EG, Moses, HL. Stromal fibroblasts in cancer initiation and progression. Nature, 432(7015), 332-7, 2004

Bhowmick, Neil A, Chytil, Anna, Plieth, David, Gorska, Agnieszka E, Dumont, Nancy, Shappell, Scott, Washington, M Kay, Neilson, Eric G, Moses, Harold L. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science, 303(5659), 848-51, 2004

Bhowmick, Neil A, Ghiassi, Mayshan, Aakre, Mary, Brown, Kimberly, Singh, Vikas, Moses, Harold L. TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc Natl Acad Sci U S A, 100(26), 15548-53, 2003 PMCID:307605

Gorska, Agnieszka E, Jensen, Roy A, Shyr, Yu, Aakre, Mary E, Bhowmick, Neil A, Moses, Harold L. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol, 163(4), 1539-49, 2003 PMCID:1868288

Chytil, Anna, Magnuson, Mark A, Wright, Christopher V E, Moses, Harold L. Conditional inactivation of the TGF-beta type II receptor using Cre:Lox. Genesis, 32(2), 73-5, 2002

Law, Brian K, Chytil, Anna, Dumont, Nancy, Hamilton, Elizabeth G, Waltner-Law, Mary E, Aakre, Mary E, Covington, Cassondra, Moses, Harold L. Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol, 22(23), 8184-98, 2002 PMCID:134072

Datta, P K, Moses, H L. STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Mol Cell Biol, 20(9), 3157-67, 2000 PMCID:85610

Law, B K, Waltner-Law, M E, Entingh, A J, Chytil, A, Aakre, M E, N??rgaard, P, Moses, H L. Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen. J Biol Chem, 275(49), 38261-7, 2000

Engel, M E, McDonnell, M A, Law, B K, Moses, H L. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem, 274(52), 37413-20, 1999

Law, B K, N??rgaard, P, Gnudi, L, Kahn, B B, Poulson, H S, Moses, H L. Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway. J Biol Chem, 274(8), 4743-8, 1999

N??rgaard, P, Law, B, Joseph, H, Page, D L, Shyr, Y, Mays, D, Pietenpol, J A, Kohl, N E, Oliff, A, Coffey, R J, Poulsen, H S, Moses, H L. Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis. Clin Cancer Res, 5(1), 35-42, 1999

Datta, P K, Chytil, A, Gorska, A E, Moses, H L. Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. J Biol Chem, 273(52), 34671-4, 1998

Engel, M E, Datta, P K, Moses, H L. RhoB is stabilized by transforming growth factor beta and antagonizes transcriptional activation. J Biol Chem, 273(16), 9921-6, 1998

Gorska, A E, Joseph, H, Derynck, R, Moses, H L, Serra, R. Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ, 9(3), 229-38, 1998

Serra, R, Moses, H L. Tumor suppressor genes in the TGF-beta signaling pathway. Nat Med, 2(4), 390-1, 1996

Alexandrow, M G, Kawabata, M, Aakre, M, Moses, H L. Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc Natl Acad Sci U S A, 92(8), 3239-43, 1995 PMCID:42141

Alexandrow, M G, Moses, H L. Transforming growth factor beta and cell cycle regulation. Cancer Res, 55(7), 1452-7, 1995

Alexandrow, M G, Moses, H L. Transforming growth factor beta 1 inhibits mouse keratinocytes late in G1 independent of effects on gene transcription. Cancer Res, 55(17), 3928-32, 1995

Kawabata, M, Chytil, A, Moses, H L. Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. J Biol Chem, 270(10), 5625-30, 1995

Kawabata, M, Imamura, T, Miyazono, K, Engel, M E, Moses, H L. Interaction of the transforming growth factor-beta type I receptor with farnesyl-protein transferase-alpha. J Biol Chem, 270(50), 29628-31, 1995

Pierce, D F, Gorska, A E, Chytil, A, Meise, K S, Page, D L, Coffey, R J, Moses, H L. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A, 92(10), 4254-8, 1995 PMCID:41922

Moses, H L, Arteaga, C L, Alexandrow, M G, Dagnino, L, Kawabata, M, Pierce, D F, Serra, R. TGF beta regulation of cell proliferation. Princess Takamatsu Symp, 24, 250-63, 1994

Serra, R, Pelton, R W, Moses, H L. TGF beta 1 inhibits branching morphogenesis and N-myc expression in lung bud organ cultures. Development, 120(8), 2153-61, 1994

Pierce, D F, Johnson, M D, Matsui, Y, Robinson, S D, Gold, L I, Purchio, A F, Daniel, C W, Hogan, B L, Moses, H L. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev, 7(12A), 2308-17, 1993

Pietenpol, J A, M??nger, K, Howley, P M, Stein, R W, Moses, H L. Factor-binding element in the human c-myc promoter involved in transcriptional regulation by transforming growth factor beta 1 and by the retinoblastoma gene product. Proc Natl Acad Sci U S A, 88(22), 10227-31, 1991 PMCID:52901

Lyons, R M, Gentry, L E, Purchio, A F, Moses, H L. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol, 110(4), 1361-7, 1990 PMCID:2116088

Moses, H L, Yang, E Y, Pietenpol, J A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell, 63(2), 245-7, 1990

Pelton, R W, Hogan, B L, Miller, D A, Moses, H L. Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Dev Biol, 141(2), 456-60, 1990

Pietenpol, J A, Holt, J T, Stein, R W, Moses, H L. Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci U S A, 87(10), 3758-62, 1990 PMCID:53982

Pietenpol, J A, Stein, R W, Moran, E, Yaciuk, P, Schlegel, R, Lyons, R M, Pittelkow, M R, M??nger, K, Howley, P M, Moses, H L. TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell, 61(5), 777-85, 1990

Yang, E Y, Moses, H L. Transforming growth factor beta 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol, 111(2), 731-41, 1990 PMCID:2116177

Barnard, J A, Beauchamp, R D, Coffey, R J, Moses, H L. Regulation of intestinal epithelial cell growth by transforming growth factor type beta. Proc Natl Acad Sci U S A, 86(5), 1578-82, 1989 PMCID:286741

Bascom, C C, Wolfshohl, J R, Coffey, R J, Madisen, L, Webb, N R, Purchio, A R, Derynck, R, Moses, H L. Complex regulation of transforming growth factor beta 1, beta 2, and beta 3 mRNA expression in mouse fibroblasts and keratinocytes by transforming growth factors beta 1 and beta 2. Mol Cell Biol, 9(12), 5508-15, 1989 PMCID:363721

Pelton, R W, Nomura, S, Moses, H L, Hogan, B L. Expression of transforming growth factor beta 2 RNA during murine embryogenesis. Development, 106(4), 759-67, 1989

Coffey, R J, Bascom, C C, Sipes, N J, Graves-Deal, R, Weissman, B E, Moses, H L. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol, 8(8), 3088-93, 1988 PMCID:363535

Coffey, R J, Sipes, N J, Bascom, C C, Graves-Deal, R, Pennington, C Y, Weissman, B E, Moses, H L. Growth modulation of mouse keratinocytes by transforming growth factors. Cancer Res, 48(6), 1596-602, 1988

Keski-Oja, J, Blasi, F, Leof, E B, Moses, H L. Regulation of the synthesis and activity of urokinase plasminogen activator in A549 human lung carcinoma cells by transforming growth factor-beta. J Cell Biol, 106(2), 451-9, 1988 PMCID:2114980

Keski-Oja, J, Raghow, R, Sawdey, M, Loskutoff, D J, Postlethwaite, A E, Kang, A H, Moses, H L. Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells. J Biol Chem, 263(7), 3111-5, 1988

Lyons, R M, Keski-Oja, J, Moses, H L. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol, 106(5), 1659-65, 1988 PMCID:2115066

Keski-Oja, J, Lyons, R M, Moses, H L. Immunodetection and modulation of cellular growth with antibodies against native transforming growth factor-beta 1. Cancer Res, 47(24 Pt 1), 6451-8, 1987


Postdoctoral Position Available
No

Postdoctoral Position Details
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Updated Date
07/27/2009