Cancer Biology

We are interested in uncovering basic molecular and cellular mechanisms of cancer origin and progression to end-stage disease. For many years the major conceptual theme in our laboratory has been the molecular pathways underlying paracrine interactions between tissue compartments, such as stromal to epithelial signals, and the role these signals play in cancer. Many of these studies have centered on the role of epidermal growth factor-like growth factors (see the page EGF-like growth factors on this website) and other growth factors in benign and malignant epithelial cell growth. These studies have included analysis of signal transduction pathways downstream from growth factor-receptor binding. We are also studying the role of calcium in tumor cell growth and survival as well as in other physiologic settings, such as bone (osteoblast) signal transduction. Our major focus has been on prostate cancer, but more recently we have been studying bladder cancer and breast cancer and have published in these areas.

Selected Publications

Freeman, M.R. Schneck, F.X., Gagnon, M., Corless, C., Soker, S., Niknejad, K., Peoples, G.E., and Michael Klagsbrun. (1995) Peripheral blood T lymphocytes and T cells infiltrating human cancers express vascular endothelial growth factor: A potential role for T cells in angiogenesis. Cancer Research 55:4140-4145.

Moses, M.A., Wiederschain, D., Loughlin, K.R., Zurakowski, D., Lamb, C.C., and Freeman, M.R. (1998) Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Research 58:1395-1399.

Adam, R.M., Borer, J.G., Williams, B.J., Eastham, J.A., Loughlin, K.R., Freeman, M.R. (1999) Amphiregulin is coordinately expressed with heparin-binding epidermal growth factor-like growth factor in the interstitial smooth muscle of the human prostate. Endocrinology 140:5866-5875.

Peng, J-G., Zhuang, L., Berger, U.V., Adam, R.M., Williams, B.J., Brown, E.M., Hediger, M.A., and Freeman, M.R. (2001) CaT1 expression correlates with tumor grade in prostate cancer. Biochemical and Biophysical Research Communications 282:729-734.

Lin, J., Hutchinson, L., Gaston, S.M., Raab, G., and Freeman, M.R. (2001) BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: A unique role for proHB-EGF in cell survival regulation. Journal of Biological Chemistry 276:30127-30132.

Soker, S., Kaefer, M., Johnson, M., Klagsbrun, M., Atala, A., and Freeman, M.R. (2001) VEGF-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype. American Journal of Pathology 159:651-659.

Kim, J., Adam, R.M., and Freeman, M.R. (2002) Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Research 62:1549-1554.

Zhuang, L., Lin, J., Lu, M.L., Solomon, K.R., and Freeman, M.R. (2002) Cholesterol-rich lipid rafts mediate Akt-regulated survival in prostate cancer cells. Cancer Research 62:2227-2231.

Adam, R.M., Danciu, T., McClellan, D.L., Borer, J.G., Lin, J., Zurakowski, D., Weinstein, M.H., Rajjayabun, P., Mellon, J.K., and Freeman, M.R. (2003) A nuclear form of the heparin-binding EGF-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Research 63:484-490.

Kim, J., and Freeman, M.R. (2003) JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. Breast Cancer Research and Treatment 79:321-328.

Kim, J., Adam, R.M., Solomon, K.R., and Freeman, M.R. (2004) Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells. Endocrinology 145:613-619.

Cinar, B., Yeung, F. Konaka, H., Mayo, M.W., Freeman, M.R. ,Zhau, H.E., and Chung, L.W.K. (2004) Identification of a negative regulatory cis-element in the enhancer core region of the prostate specific antigen (PSA) promoter: Implications for intersection of androgen receptor and NF-kB signaling in prostate cancer cells. Biochemical Journal 379:421-431.

Orsala, A., Estrada, C.R., Nguyen, H.T., Retik, A.B., Freeman, M.R., Peters, C.A. and Adam, R.M. (2005) Growth and stretch response of human exstrophy bladder smooth muscle cells: Molecular evidence of normal intrinsic function. BJU, International (British Journal of Urology). 95:144-148.

Zhuang, L., Kim, J., Adam, R.M., Solomon, K.R., and Freeman, M.R. (2005) Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. Journal of Clinical Investigation 115:959-968.

Cinar, B., De Benedetti, A., and Freeman, M.R. (2005) Post-transcriptional regulation of the androgen receptor by the mammalian target of rapamycin. Cancer Research 65:2547-2553.

Marcus, K., Johnson, M., Adam, R.M., O’Reilly, M.S., Donovan, M., Atala, A., Freeman, M.R., and Soker, S. (2005) Tumor cell-associated neuropilin-1 and VEGF expression as determinants of tumor growth in neuroblastoma. Neuropathology 25:178-187.

Kim, J., Lin, J., Adam, R.M., Lamb, C., Shively, S.B., and Freeman, M.R. (2005) An oxidative stress mechanism mediates chelerythrine-induced heparin-binding EGF-like growth factor ectodomain shedding. Journal of Cellular Biochemistry 94:39-49.

MacLellan, D.L., Steen, H., Adam, R.M., Garlick, M., Zurakowski, D., Gygi, S.P., Freeman, M.R. and Solomon, K.R. (2005) A quantitative proteomic analysis of growth factor-induced compositional changes in lipid rafts of human smooth muscle cells. Proteomics 5:4733-4742.

Kim, J., Adam, R.M., and Freeman, M.R. (2005) Trafficking of nuclear HB-EGF into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Research 65:8242-8249.

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