Title |
Endothelial Transdifferentiation of Invasive Tumor Cells
|
Institution |
CHILDREN'S MEMORIAL HOSPITAL (CHICAGO), CHICAGO, IL
|
Principal Investigator |
HENDRIX, MARY
|
NCI Program Director |
Suresh Mohla
|
Cancer Activity |
Tumor Biology
|
Division |
DCB
|
Funded Amount |
$393,942
|
Project Dates |
05/01/1993 - 04/30/2012
|
Fiscal Year |
2010
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Cancer (100.0%)
Metastasis (100.0%)
|
Melanoma (100.0%)
|
Research Type |
Cancer Progression and Metastasis
|
Abstract |
DESCRIPTION (provided by applicant): During embryonic development, the
formation of primary vascular networks occurs by vasculogenesis -- the in situ
differentiation of progenitor cells to endothelial cells that organize into a
primitive network. The subsequent remodeling of the vasculogenic network into a
functionally efficient vasculature occurs through angiogenesis -- the sprouting
of new capillaries from a preexisting network. We have introduced the term
"vasculogenic mimicry" to describe the unique ability of aggressive melanoma
tumor cells to form tubular structures and patterned networks in 3-D culture,
which "mimics" the pattern of embryonic vasculogenic networks and recapitulates
the patterned networks seen in patients' aggressive tumors -- correlating with
poor prognosis. The molecular profile of these aggressive tumor cells suggests
that they have a deregulated genotype, capable of expressing an
endothelial-like phenotype. Our preliminary studies indicate that: 1)
aggressive melanoma cells express VE-cadherin (exclusively expressed by
endothelial cells); 2) aggressive tumor cells produce an extracellular matrix
(ECM) that induces poorly aggressive melanoma cells to form vasculogenic
networks; and 3) aggressive melanoma cells participate in the revascularization
of an ischemic limb model, thus illustrating their endothelial stem cell
plasticity. The proposed studies advance observations made during the current
funding period regarding the embryonic-like phenotype of aggressive melanoma
cells: Aim 1: Determine the functional significance of VE-cadherin expression
in human melanoma tumor cells engaged in endothelial transdifferentiation and
vasculogenic mimicry. Aim 2: Identify the key molecular components produced by
aggressive melanoma tumor cells that induce poorly aggressive melanoma cells to
form vasculogenic networks and mimic endothelial cells. Aim 3: Investigate the
stem cell plasticity of aggressive melanoma tumor cells for their potential to
re-vascularize tissues in animal models of wound healing and ischemia. The data
generated from these novel studies will provide new molecular markers for
clinical diagnosis and new concepts regarding the trarisendothelial
differentiation of aggressive melanoma tumor cells and their stem cell
plasticity. |