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Obesity and Cancer Program

The laboratory projects includes studies on crosstalk between growth factor and steroid receptors in cancer progression and development of anti-cancer targeted strategies.

Program Details | Biography Details | Publications

  OBESITY AND CANCER

PROGRAM DETAILS

The prevalence of obesity has markedly increased over the past two centuries. In the United States, approximately 66% of adults are overweight and 31% are obese, while globally overweight population has exceeded 1 billion. Epidemiological data gathered over the past two decades clearly demonstrate that obesity in adults is associated with increased risk of numerous disease, including some forms of cancer.

While the impact of excess body weight on the development of cardiac disease and diabetes has been well documented, the link between obesity and carcinogenesis is just being recognized. How exactly excess body fat can promote neoplastic transformation is not clear. We hypothesized that tumor formation might be induced or accelerated by adipokines--biologically active substances produced by the fat tissue.

The major adipokine--leptin is a pluripotent cytokine that controls energy balance and food intake acting in the brain, but can also modulate the function of several peripheral organs and tissues. Leptin levels are significantly elevated in obese individuals, and are higher in women than in man.

According to studies from our and other laboratories, leptin is able to induce the growth and transformation of cancer, but not normal, cells. In addition, leptin can stimulate cell invasion and tumor metastasis. Furthermore, high concentrations of leptin can interfere with different anti-cancer cancer therapies.

Interestingly, leptin is produced not only by adipose tissue, but also by cancer cells themselves. Notably, cancer cells can secrete leptin in response to obesity-related stimuli, such as hyperinsulineamia, high levels of estrogens, or hypoxia. We are studying the molecular mechanisms of leptin overexpression in cancer as well as diagnostic and prognostic value of the leptin system in different types of cancer. Another aspect of the program is to design and validate molecular therapeutics targeting leptin activity in tumor cells.

In addition, we are developing projects to study how obesity might affect the response of breast cancer patients to chemo- and hormonal therapies, and how diet might modulate the expression of cancer-related genes.

  OBESITY AND CANCER

BIOGRAPHY DETAILS

Eva Surmacz, Ph.DAssociate Professor of Biology and Director of the Obesity and Cancer Program at S.H.R.O is an internationally recognized expert in cancer biology. Over the past 12 years, Dr. Surmacz's research has been supported by the NIH, Department of Defense Breast Cancer Research Program, several private foundations and organizations, and the pharmaceutical industry.

Alessandra Auriemma, M.D. SHRO Research Scholar and Fellow in Medical Oncology at the University of Verona.

Sandra Cascio, Ph.D., SHRO Research Scholar

Marianna Terrasi, B.S., SHRO Research Scholar and Ph. D. Student in the Oncobiology Program at the University of Palermo.

Viviana Bartella, Pharm.D., Ph.D. SHRO Research Scholar and Fellow in Clinical Pathology Specialization Program at University of Calabria.

Elena Fiorio, M.D., SHRO Research Scholar and a Fellow in Medical Oncology at the University of Verona.

  OBESITY AND CANCER

PUBLICATIONS (2003-2008)

Knappe, D., Otvos, L., De Pascali, F., Cassone, M. Scolaro, L., Abbadessa, G., Carillo-Infante, C., Kiani, M.F., Donelson, F., Hoffmann, R., Surmacz, E. Drug development-targeted screening of leptin agonist glycopeptides. Int. J. Peptide Res., in press, 2008.

Lanzino, M., Garofalo, C., Morelli, C., Le Pera, M., Zupo, S., McPhaul, M., Surmacz, E., Ando, S., Sisci, D. Insulin receptor substrate 1 modulates androgen receptor transcriptional activity and stability in breast cancer cells. Breast Cancer Res. Treatm., Epubl June 4, 2008.

Otvos Jr, L., Terrasi, M., Cascio, S., Cassone, M., Knappe, D., Stawikowski, M., Cudic, P., Wade, J.D., Hoffmann, R., Surmacz, E. Synthetic leptin fragments and their designer analogs are partial and full agonists of cells expressing the leptin receptor. BBA Mol. Cell Res., 1783:1745-54. Epub May 21, 2008.

Bartella, V., Casio, S., Auriemma, A., Fiorio, E., Russo, A., Surmacz, E. Insulin-dependent leptin expression in breast cancer cells. Cancer Res. 68:4919-27, 2008.

Cascio, S., Bartella, V., Auriemma, A., Russo, A., Giordano, A., Surmacz, E. Mechasnism of leptin expression in breast cancer cells: Role of hypoxia-inducible factor 1alpha. Oncogene 27:540-7, 2008.
Surmacz, E, Koda, M. Leptin as a novel marker in breast and colorectal cancer. In: Leptin and leptin antagonists. Ed. Arieh Gertler. Landes Bioscience Publ. in press, 2008.

Russo, A., Calò, V., Bruno, V., Schirò, V., Agnese, V., Cascio, S., Foddai, E., Fanale, D., Rizzo, S., Di Gaudio, F., Gulotta, E., Surmacz, E., Di Fede, G., Bazan, V. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res. Treatm., Epubl. Jan 29, 2008.

Russo, A., Calo, V., Augello, C., Bruno, L., Agnese, V., Schiro, V., Barbera, F., Cascio, S., Foddai, E., Badalamenti, G., Intrivici, C., Cajozzo, M., Gulotta, G., Surmacz, E., Colucci, G., Gebbia, N., Bazan, V. 4843delC of the BRCA1 gene is a possibile founder mutation in Southern Italy (Sicily). Ann. Oncol. 18: vi99-102, 2007.

Ferla, R., Calo, V., Cascio, S., Rinaldi, G., Badelamenti, G., Carreca, I., Surmacz, E., Colucci, G., Bazan, V., Russo, A. Founder mutations in BRCA1 and BRCA2 genes. Ann. Oncol. 18: vi93-98, 2007.

Koda, M., Sulkowska, M., Kanczuga-Koda, L., Cascio, S., Colucci, G., Russo, A., Surmacz , E., Sulkowski, S. Expression of the obesity hormone leptin and its receptor correlates with hypoxia-inducible factor-1α in human colorectal cancer. Ann. Oncol. 18: vi116-vi119, 2007.

Sisci, D., Morelli, C., Cascio, S., Lanzino, M., Garofalo, C., Reiss, K., Garcia, M., Russo, A., Ando, S., Surmacz, E. The estrogen receptor-alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships. Ann. Oncol. Suppl 6:vi81-5, 2007.

Surmacz, E. Obesity hormone leptin-a new target in breast cancer? Breast Cancer Res. 9:301, 2007.

Sisci, D., Surmacz, E. Crosstalk between IGF-I signaling and steroid hormone receptors in breast cancer. Curr Pharm Des. 13:705-17, 2007.

Russo A, Calo V, Agnese V, Bruno L, Corsale S, Augello C, Gargano G, Barbera F, Cascio S, Intrivici C, Rinaldi G, Gulotta G, Macaluso M, Surmacz E, Giordano A, Gebbia N, Bazan V. BRCA1 genetic testing in 106 breast and ovarian cancer families from southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat. E-publ. Jan 13, 2007.

Cascio, S., Bartella, V., Garofalo, C., Russo, A., Giordano, A., Surmacz, E. Insulin-like growth factor 1 differentially regulates estrogen receptor-dependent transcription at ERE and AP-1 sites in breast cancer cells. J. Biol. Chem, 282:3498-506, 2007.

Koda, M., Sulkowska, M., Kanczuga-Koda, L., Surmacz, E., Sulkowski, S. Overexpression of obesity hormone leptin in human colorectal cancer. J. Clin. Path., 60:902-6, 2007.

Sisci, D., Morelli, C., Garofalo, C., Romeo, F., Morabito, L., Casaburi, F., Middea, E., Brunelli, E., Cascio, C., Andò, S., Surmacz, E. Expression of nuclear insulin receptor substrate 1 (IRS-1) in breast cancer. J. Clin. Path., e-published Aug 1, 2006.

Augello, C., Bruno, L., Bazan, V., Calo`, V., Agnese, V., Corsale, S., Cascio, S., Gargano, M., Terrasi, M., Barbera, F., Fricano, S., Adamo, B., Valerio, M.R., Colucci, G., Surmacz, E., Russo, A. Y179C, F486L and N550H are BRCA1 variants that may be associated with breast cancer in a Sicilian family: results of a 5-year GOIM (Gruppo Oncologico dell’Italia Meridionale) prospective study Ann Oncol. 17 (Suppl 7): vii30–vii33, 2006.

Garofalo, C., Koda, M., Cascio, S., Sulkowska, M., Kanczuga-Koda, L., Golaszewska, J., Russo, A., Sulkowski, S, Surmacz, E. Increased expression of leptin and the leptin receptor in primary and metastatic breast cancer: possible role of obesity-related stimuli. Clin. Cancer Res., 12: 1447-53, 2006.

Cesarone, G., Garofalo, C., Abrams, M., Igoucheva, O., Alexeev, V., Yoon, K., Surmacz, E., Wickstrom, E. RNAi-mediated knockdown of Insulin Receptor Substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells. J. Cell. Bioch., e-publ. Jan 26, 2006.

Augello, C., Gregorio, V., Bazan, V., Cammareri, P., Agnese, V., Cascio, S., Corsale, S., Calò, V., Gullo, A., Sisto, P.S., Rinaldi, G., Morello, V., Gerbino, A., Tomasino, R.M., Macaluso, M., Surmacz, E., Russo, A. TP53 and p16ink4a, but not H-Ki-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas, J. Cell. Physiol., 207: 654-9, 2006.

Chen, J., Wu, A., Sun, H., Drakas, R., Garofalo, C., Cascio, S., Surmacz, E., Baserga, R. Functional significance of IGF-1-mediated nuclear translocation of the insulin receptor substrate 1 and beta-catenin. J. Biol. Chem., 280:29912-20, 2005.

Russo, A., Corsale, S., Agnese, V., Macaluso, M., Cascio, S., Bruno, L., Surmacz, E., Dardanoni, G., Valerio, M.R., Vieni, S., Restivo, S., Fulfaro, F., Tomassio R.M., Gebbia, N., Bazan, V. TP 53 mutations and S-phase fraction but not DNA-ploidy are independent prognositic indicators in laryngeal squamous cell carcinoma. J. Cell. Physiol., e-publ. June 17, 2005.

Garofalo, C., Surmacz, E. Leptin and cancer. J. Cell. Physiol., e-publ. Aug. 18, 2005.

Del Rincon, S.V., Guo, Q., Morelli, C., Shu, H-Y., Surmacz, E., Miller, W. H. Retinoic acid-mediated degradation of IRS-1 by the ubiquitin-proteasome pathway involves a PKC-dependent mechanism. Oncogene, 23:9269-9279, 2004.

Morelli, C., Garofalo, C., Sisci, D., delRincon, S., Cascio, S., Xu, S., Vecchione, A., Sauter, ER., Miller, W., Surmacz, E. Nuclear insulin receptor substrate 1 interacts with estrogen receptor alpha at ERE promoters. Oncogene 23:7517-7526, 2004.

Garofalo, C., Sisci, D., Surmacz, E. Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells.Clin. Cancer Res., 10:6466-6475, 2004.

Surmacz, E., Bartucci, M. Differential function of insulin-like growth factor I (IGF-I) in estrogen receptor (ER)-positive and ER-negative breast cancer cells. J. Exp. Clin. Cancer Res.,23: 385-394, 2004.

Sauter, E. R., Garofalo, C., Hewett, J., Morelli, C., Surmacz, E. Leptin expression in breast nipple aspirate fluid (NAF) is influenced by body mass index (BMI) in premenopausal women. Hormone Met. Res. 36: 336-340, 2004.

Koda, M., Sulkowski, S., Kanczuga-Koda, L., Surmacz, E., Sulkowska, M. Expression of ERalpha, ERbeta, and Ki-67 in primary tumors and lymph node metastases in breast cancer. Onc. Rep., 11: 753-759, 2004.

Mauro, L., Surmacz, E. IGF-I receptor, cell-cell adhesion, tumor development and progression. J.Mol. Histology, 35: 247-253, 2004.

Koda, M., Sulkowski, S., Garofalo, C., Kanczuga-Koda, L., Sulkowska, M., Surmacz, E. Expression of the insulin-like growth factor I receptor in primary breast cancer and lymph node metastases: correlations with estrogen receptors alpha and beta. Hormone Metab. Res. 35: 794-801, 2003.

Surmacz, E. Growth factor receptors as therapeutic targets: Strategies to inhibit the insulin-like growth factor I receptor. Oncogene, 22: 6589-6597, 2003. Morelli, C., Garofalo, C., Bartucci, M., Surmacz, E. Estrogen receptor-alpha regulates the degradation of the insulin receptor substrates 1 and 2 in breast cancer cells. Oncogene, 22: 4007-4016, 2003.

Surmacz, E. Leptin--a growth factor in normal and malignant cells and for normal mammary development. Commentary. Women's Oncol. Rev. 3: 129-130, 2003. Mauro, L., Salerno, M., Morelli, C., Boterberg, T., Bracke, M., Surmacz, E. Role of the IGF-I receptor in the regulation of cell-cell adhesion. Implications in cancer development and progression. J.Cell. Physiol. 194: 108-116, 2003.

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