Steven Rosenzweig, PhD
1980 Ph.D., University of Toronto
Office: BSB 313G
Growth factor dysregulation in cancer.
Insulin-like growth factor (IGF) receptor crosstalk to vascular endothelial growth factor (VEGF) and metastatic signaling cascades; VEGF signaling to HEF1 and invadopodia formation; and IGF-binding protein structure and function.
We are studying the dysregulation of the insulin-like growth factor (IGF) system in cancer. In breast cancer and head and neck squamous cell carcinoma cells, we are examining IGF-1 receptor crosstalk to vascular endothelial growth factor (VEGF) signaling in mediating enhanced tumorigenicity and metastasis.
Using retinal pigment epithelial cells as a model, we are studying the interplay between IGF-1 receptor signaling and hypoxia in the regulation of vascular endothelial growth factor production and the loss of intercellular tight junctions. These studies are designed to better understand the contributions of these factors to the choroidal neovascularization accompanying age-related macular degeneration.
An underlying theme of our research is to develop inhibitors of IGF signaling. Toward this end we are employing a number of complementary strategies to develop IGF antagonists using the IGF-binding proteins (IGFBPs) as lead compounds. The IGFBPs are a class of six homologous secretory proteins, which function to block access of the IGFs to the IGF-1 receptor. For these analyses, we are using IGFBP-2 as a template for studies aimed at defining the binding domain for IGF-1. The IGFBPs interact with a specific binding domain on IGF-1 that is distinct from its receptor binding domain. These studies have profound implications for the development of IGF-1 antagonists by designing small molecular weight analogs, structurally identical to the binding site for use in inhibiting the growth of IGF-dependent tumors. These studies also have important applications toward defining the IGF-1 binding domain on the IGF-1 receptor and the development of IGF-1 receptor antagonists.
Toward this end, we are collaborating with Professor H.S. Atreya in the Biomolecular NMR Laboratory at the Indian Institute of Science, Bangalore, India.
Recent Publications | Additional Publications
1. Rosenzweig SA, Atreya HS. Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem Pharmacol. 2010 Oct 15;80(8):1115-24. Epub 2010 Jun 23. Review. PMID:20599789
2. Swain M, Slomiany MG, Rosenzweig SA, Atreya HS. High-yield bacterial expression and structural characterization of recombinant human insulin-like growth factor binding protein-2. Arch Biochem Biophys. 2010 Sep 15;501(2):195-200. Epub 2010 Jun 10. PMID:20541521
3. Lucas JT Jr, Salimath BP, Slomiany MG, Rosenzweig SA. Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent. Oncogene. 2010 May 24. [Epub ahead of print] PubMed PMID: 20498643. [pdf]
4. Mulligan JK, Rosenzweig SA, Young MR. Tumor secretion of VEGF induces endothelial cells to suppress T cell functions through the production of PGE2. J Immunother. 2010 Feb-Mar;33(2):126-35. PubMed PMID: 20145550.
5. Swain M, Thirupathi R, Krishnarjuna B, Eaton EM, Kibbey MM, Rosenzweig SA, Atreya HS. Spontaneous and reversible self-assembly of a polypeptide fragment of insulin-like growth factor binding protein-2 into fluorescent nanotubular structures. Chem Commun (Camb). 2010 Jan 14;46(2):216-8. Epub 2009 Nov 12. PubMed PMID: 20024330. [pdf]
6. Mulligan JK, Day TA, Gillespie MB, Rosenzweig SA, Young MR. Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions. Hum Immunol. 2009 Jun;70(6):375-82. Epub 2009 Feb 12. PubMed PMID: 19480853; PubMed Central PMCID: PMC2746465.