Our laboratory has described a new phenomenon, tumor Vasculogenesis, whereby tumor cells themselves (in the absence of endothelial cells), form vascular channels and tubular networks which facilitate tumor perfusion independent of classical angiogenesis. Preliminary studies utilizing prostate tumors and neoplastic prostate cell lines strongly support the concept that """"""""vasculogenic mimicry"""""""" is also exhibited by aggressive prostatic neoplasms. The overall objective of this proposed research, therefore, is to determine the key molecular mechanisms underlying this phenomenon in tumors of the prostate.
Specific Aim 1 : Characterize the cellular and molecular phenotype of the aggressive prostate cancer cells undergoing vasculogenic mimicry. Hypothesis: Invasive and metastatic prostate cancer cells (but not normal prostate epithelium) undergo vasculogenic mimicry and form vascular channels and tubular networks, which can perfuse the tumor independent of or supplemental to angiogenesis.
Specific Aim 2 : Examine the molecular interactions between the epithelial and fibroblast-like subpopulations comprising heterogeneous prostate cancers, resulting in vasculogenic mimicry. Hypothesis: A highly regulated cooperativity between the epithelial and fibroblast-like subpopulations is necessary for vasculogenic mimicry in heterogeneous prostate tumors.
Specific Aim 3 : Determine the role/importance of specific matrix metalloproteinases (MMPs) in prostatic vasculogenic mimicry. Hypothesis: Specific MMPs are critical in the formation of vascular channels and tubular networks by aggressive prostate cancer cells. Significance: The hypothesized presence of tumor- cell lined channels intimately investing neoplasms of the prostate gland, together with their presumptive anastomosis with endothelial-lined vessels of the tumor, provides: 1) a potential new route by which metastases may spread to distant sites, and 2) a means of providing, or supplementing exchange between the tumor and the blood vascular system. As the fundamental cell and molecular mechanisms are identified which underlie the formation, morphology, and functional relationships between these two vascular compartments, it is highly likely that novel strategies will be identified for interfering clinically with both tumor growth and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088043-04
Application #
6633831
Study Section
Special Emphasis Panel (ZRG1-MEP (01))
Program Officer
Mohla, Suresh
Project Start
2000-09-06
Project End
2004-04-30
Budget Start
2003-07-01
Budget End
2004-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$90,718
Indirect Cost
Name
University of Iowa
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Seftor, Richard E B; Hess, Angela R; Seftor, Elisabeth A et al. (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181:1115-25
Chunthapong, Jirapat; Seftor, Elisabeth A; Khalkhali-Ellis, Zhila et al. (2004) Dual roles of E-cadherin in prostate cancer invasion. J Cell Biochem 91:649-61
Hendrix, Mary J C; Seftor, Elisabeth A; Hess, Angela R et al. (2003) Molecular plasticity of human melanoma cells. Oncogene 22:3070-5
Hess, Angela R; Seftor, Elisabeth A; Seftor, Richard E B et al. (2003) Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Res 63:4757-62
Hendrix, Mary J C; Seftor, Elisabeth A; Kirschmann, Dawn A et al. (2003) Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann N Y Acad Sci 995:151-61
Seftor, Richard E B; Seftor, Elisabeth A; Kirschmann, Dawn A et al. (2002) Targeting the tumor microenvironment with chemically modified tetracyclines: inhibition of laminin 5 gamma2 chain promigratory fragments and vasculogenic mimicry. Mol Cancer Ther 1:1173-9
Sharma, Navesh; Seftor, Richard E B; Seftor, Elisabeth A et al. (2002) Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate 50:189-201
Seftor, R E; Seftor, E A; Koshikawa, N et al. (2001) Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res 61:6322-7