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Role of transforming growth factor-ß(TGFß) in human cancer. targeting TGFß signaling as cancer therapyFor the past 15 years. my laboratory has focused on elucidating the cellular and molecular pathophysiology of aero-digestive tract cancers. particularly squamous cell carcinomas of the head-&-neck. lung and esophagus. Our most important contributions have revolved around the role of the Transforming Growth Factor-ß (TGFß) signaling pathway in squamous carcinogenesis. Because TGFß appears to play similar roles in many cancers. we have expanded our disease focus to include breast-. colon-. endometrial- and cervical cancer. We have made a number of important contributions to our understanding of how these cancers escape from normal physiological cell cycle control and regulation of differentiation by TGFß. We were among the first to identify TGFß as an extremely potent physiological auto- and/or paracrine inhibitor of cell cycle progression in normal keratinocytes (the cell of origin of squamous cell carcinomas). We then showed that most common carcinomas are refractory to TGFß-mediated cell cycle arrest. Because the escape from TGFß control appears to be critical for cancer development. we have focused most of our recent efforts on elucidating the molecular mechanisms underlying this escape. We were the first to show that TGFß resistance is the result of gene inactivation. One of our most important findings is that intragenic mutations can occur in the TGFß type II as well as type I receptors (TßR). Moreover. these TßR mutants are defective in terms of their signaling ability . Since then. we extended these studies to determine the spectrum of genetic alterations of the TßR genes in aero-digestive tract cancers as well as in other TGFß-refractory common human neoplasms. Thus far. our studies of the TßR-II gene in primary tumor specimens have shown that. although missense or nonsense mutations are probably relatively uncommon. loss of mRNA- or protein expression occurs at much higher frequency in esophageal-. endometrial and small-cell lung cancers. Our current strategy is to develop the tools that will allow us to identify. in individual primary cancers. the specific molecular lesion that has resulted in TGFß resistance. In addition. we are studying the biological significance of TGFß resistance using tissue microarray technology. For example. it is likely that TGFß-refractory cancers are more invasive and/or metastatic. and perhaps more resistant to therapy than TGFß-responsive cancers. Last but not least. we now have all of the reagents and technology in place to embark on a major new project to develop a novel form of cancer therapy based on inhibition of TGFß signaling. This idea is based on the overwhelming experimental evidence that many cancers produce large amounts of bioactive TGFß that enhance their ability to invade and metastasizes. stimulate angiogenesis and suppress anti-tumor immunity. By blocking these effects of tumor-derived TGFß on normal cells in their microenvironment. we hope to significantly complement and potentiate the efficacy of conventional cytotoxic forms of cancer therapy. Specifically. we are testing the activity of selective and potent inhibitors of TGFß receptor kinases using a number of specific in vitro and in vivo assays. with the ultimate goal of taking the most promising and safest of these compounds into clinical trial. Selected PublicationsHu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y. (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 15(1):9-20. Tan AR, Alexe G, Reiss M. (2008) Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat. 115(3):453-95. Bharathy S, Xie W, Yingling JM, Reiss M. (2008) Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res. 68(6):1656-66. Haffty BG, Yang Q, Moran MS, Tan AR, Reiss M. (2008) Estrogen-dependent prognostic significance of cyclooxygenase-2 expression in early-stage invasive breast cancers treated with breast-conserving surgery and radiation. Int J Radiat Oncol Biol Phys. 71(4):1006-13. Hall B, Chen W, Reiss M, Foran DJ. (2007) A clinically motivated 2-fold framework for quantifying and classifying immunohistochemically stained specimens. Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. 10(Pt 2):287-94. Padgett RW, Reiss M. (2007) TGFbeta superfamily signaling: notes from the desert. Yates B, Zetterberg C, Rajeev V, Reiss M, Rittling SR. (2007) Promoter-independent regulation of vimentin expression in mammary epithelial cells by val(12)ras and TGFbeta. Exp Cell Res. 313(17):3718-28. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D. (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 24(36):5652-7. Alexe G, Alexe S, Axelrod DE, Bonates TO, Lozina II, Reiss M, Hammer PL. (2006) Breast cancer prognosis by combinatorial analysis of gene expression data. Breast Cancer Res. 8(4):R41. Lee HJ. Liu H. Goodman C. Ji Y. Maehr H. Uskokovic M. Notterman D. Reiss M. Suh N. (2006) Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer. Biochem Pharmacol. 72(3):332-43. Lee HJ. Wislocki A. Goodman C. Ji Y. Ge R. Maehr H. Uskokovic M. Reiss M. Suh N. (2006) A novel vitamin D derivative activates bone morphogenetic protein signaling in MCF10 breast epithelial cells. Mol Pharmacol. 69(6):1840-8. Abu-Khalaf MM. Windsor S. Ebisu K. Salikooti S. Ananthanarayanan G. Chung GG. DiGiovanna MP. Haffty BG. Abrams M. Farber LR. Hsu AD. Reiss M. Zelterman D. Burtness BA. (2005) Five-year update of an expanded phase II study of dose-dense and -intense doxorubicin. paclitaxel and cyclophosphamide (ATC) in high-risk breast cancer. Oncology. 69(5):372-83.
Uemura M. Swenson ES. Gaca MD. Giordano FJ. Reiss M. Wells RG. (2005) Smad2
and Smad3 play different roles in rat hepatic stellate cell function and
alpha-smooth muscle actin organization. Subramanian G. Schwarz RE. Higgins L. McEnroe G. Chakravarty S. Dugar S. Reiss M. (2004) Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. Cancer Res. 64(15):5200-11. Chen W. Reiss M. Foran DJ. (2004) A prototype for unsupervised analysis of tissue microarrays for cancer research and diagnostics. IEEE Trans Inf Technol Biomed. 8(2):89-96. Ge R. Rajeev V. Subramanian G. Reiss KA. Liu D. Higgins L. Joly A. Dugar S. Chakravarty J. Henson M. McEnroe G. Schreiner G. Reiss M. (2004) Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling. Biochem Pharmacol. 68(1):41-50. Alexe G. Alexe S. Liotta LA. Petricoin E. Reiss M. Hammer PL. (2004) Ovarian cancer detection by logical analysis of proteomic data. Proteomics. 4(3):766-83. Selvamurugan N. Kwok S. Alliston T. Reiss M. Partridge NC. (2004) Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components. Smad2 and Runx2. J Biol Chem. 279(18):19327-34. Pasche B. Kaklamani V. Hou N. Young T. Rademaker A. Peterlongo P. Ellis N. Offit K. Caldes T. Reiss M. Zheng T. (2004) TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J Clin Oncol. 22(4):756-8. Xavier S. Piek E. Fujii M. Javelaud D. Mauviel A. Flanders KC. Samuni AM. Felici A. Reiss M. Yarkoni S. Sowers A. Mitchell JB. Roberts AB. Russo A. Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone. J Biol Chem. (2004)279(15):15167-76. Xie W. Bharathy S. Kim D. Haffty BG. Rimm DL. Reiss M. (2003) Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis. Oncol Res. 14(2):61-73. Bou-Khalil J. Rose M. Psyrri A. D'Andrea E. Medoff E. Staugaard-Hahn C. Holtkamp C. Gran S. Pezzimente J. Snyder E. Cooper D. Haffty B. Reiss M. Burtness B. (2003) Sequential high-dose alkylating therapy and stem cell support for high-risk stage III breast cancer. Breast J. 9(6):472-7. Xie W. Rimm DL. Lin Y. Shih WJ. Reiss M. (2003) Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J. 9(4):302-12. Felici A. Wurthner JU. Parks WT. Giam LR. Reiss M. Karpova TS. McNally JG. Roberts AB. (2003) TLP. a novel modulator of TGF-beta signaling. has opposite effects on Smad2- and Smad3-dependent signaling. EMBO J. 22(17):4465-77. Song K. Cornelius SC. Reiss M. Danielpour D. (2003) Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-beta by phosphatidylinositol 3-kinase/Akt-dependent suppression of the activation of Smad3 but not Smad2. J Biol Chem. 278(40):38342-51. Loomis R. Carbone R. Reiss M. Lacy J. (2003) Bcl-2 antisense (G3139. Genasense) enhances the in vitro and in vivo response of Epstein-Barr virus-associated lymphoproliferative disease to rituximab. Clin Cancer Res. 9(5):1931-9. Liu C. Gaca MD. Swenson ES. Vellucci VF. Reiss M. Wells RG. (2003) Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta ) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. J Biol Chem. 278(13):11721-8. |
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