The major goal of our research is to define the mechanism(s) that regulate the process of metastasis, and use this knowledge to design innovative hypothesis-based therapies. Metastasis is a highly selective process that is regulated by multiple interrelated mechanisms whose outcome is dependent upon both the intrinsic properties of tumor cells and the host response. Signals from autocrine or paracrine pathways, alone or in combination, may regulate tumor growth and metastasis with the eventual outcome dependent on a balance of stimulatory and inhibitory factors. Recent data from our laboratory demonstrate that the organ microenvironment can modulate gene expression of growth and angiogenic factors in tumor cells in an organ site specific manner. Our analyses of different human metastatic melanoma cell variants demonstrated a direct correlation between the levels of interleukin-8 (IL-8) mRNA expression and protein secretion with metastatic phenotype in nude mice. Preliminary data from our laboratory and others suggest that IL-8 is an obligate autocrine growth, motility and angiogenic factor for melanoma cells. In this application we propose to test the hypothesis that autocrine production of IL-8 and its receptors and their regulation by organ specific cytokines are important determinant in melanoma growth and metastasis.
Three specific aims will be pursued: First, we will determine the functional significance of the autocrine production of IL-8 and its receptors on the expression of cellular phenotypes associated with melanoma growth and metastasis. Second, we will analyze whether the organ microenivronments can differentially modulate the expression of IL-8 and its receptors in metastatic melanoma cells. Third, we will determine whether the expression of IL-8 correlates with the clinical grade of human melanoma tumor specimens. The knowledge gained from this research will extend our basic and clinical understanding of the mechanism(s) regulating the process of melanoma tumor growth and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA072781-04
Application #
6376331
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Ault, Grace S
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$102,857
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Sadanandam, A; Sidhu, S S; Wullschleger, S et al. (2012) Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. Br J Cancer 107:501-7
Singh, Seema; Wu, Sheng; Varney, Michelle et al. (2011) CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvasc Res 82:318-25
Varney, Michelle L; Singh, Seema; Li, Aihua et al. (2011) Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer Lett 300:180-8
Wu, S; Singh, R K (2011) Resistance to chemotherapy and molecularly targeted therapies: rationale for combination therapy in malignant melanoma. Curr Mol Med 11:553-63
Sadanandam, Anguraj; Varney, Michelle L; Singh, Seema et al. (2010) High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis. Int J Cancer 127:1373-83
Nannuru, Kalyan C; Futakuchi, Mitsuru; Varney, Michelle L et al. (2010) Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface. Cancer Res 70:3494-504
Nannuru, Kalyan C; Singh, Rakesh K (2010) Tumor-stromal interactions in bone metastasis. Curr Osteoporos Rep 8:105-13
Wilson, Thomas J; Nannuru, Kalyan C; Futakuchi, Mitsuru et al. (2010) Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1. Cancer Lett 288:162-9
Singh, Seema; Sadanandam, Anguraj; Varney, Michelle L et al. (2010) Small interfering RNA-mediated CXCR1 or CXCR2 knock-down inhibits melanoma tumor growth and invasion. Int J Cancer 126:328-36
Sadanandam, Anguraj; Rosenbaugh, Erin G; Singh, Seema et al. (2010) Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis. Microvasc Res 79:1-9

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