Newly formed blood vessels fail to mature into fully functional vessels in tumors due to the chronically angiogenic microenvironment. The functional impairment of these vessels hampers drug delivery, thereby diminishing the efficacy of antitumor therapies. Excessive vessel permeability associated with tumors also allows tumor cell invasion into the circulation facilitating metastatic spreading. Therefore, the ability to conrol vessel maturity in tumors provides a potential therapeutic opportunity. The long-term goal of this study is to understand the molecular basis for vascular maturation. Our recent studies uncovered an essential role of the small GTPase R-Ras in establishment of mature, functional blood vessels in tumors. Thus, R-Ras promotes normalization of the tumor vasculature. Now, the important new objective of this investigation is to determine the molecular pathway for R-Ras-mediated vessel regulation so that new molecular targets may be identified for controlling the tumor vasculature for therapeutic advantage. R-Ras enhances vascular integrity through regulation of VE-cadherin. Our recent studies also show that R-Ras attenuates VEGF signaling in endothelial cells by inhibiting VEGFR2 internalization upon VEGF stimulation. Furthermore, R-Ras not only promotes endothelial cell-pericyte association but also facilitates intercellular signaling between the two cell types via TGF-beta and Jagged1-mediated Notch signaling. These pathways promote endothelial cell quiescence and mural cell differentiation;therefore, they are important for vessel maturation. Based on these observations, we propose a hypothesis that R-Ras orchestrates these pathways to redirect nascent tumor vessel formation from an angiogenic sprouting/branching process to a maturation process. In this proposal, we will investigate the significance and precise roles of the R-Ras pathways during tumor vascularization.
In Aim 1, we will identify and characterize the key signaling pathways mediating the R-Ras effects on endothelial cells and pericytes in a series of in vitro experiments using various culture/coculture systems.
In Aim 2, we will validate the findings from Aim 1 in various animal models to determine the role of these mechanisms during the establishment of functional tumor vessels. The proposed studies will provide an important insight into the molecular basis for the vascular normalization phenomenon and its implications in tumor malignancy and therapies.

Public Health Relevance

Blood vessels develop abnormally in tumors due to impaired vessel maturation process. This vascular abnormality causes clinical problems such as inadequate drug delivery and tumor metastasis. This application proposes to investigate cellular signaling pathways important for vessel maturation in order to address how we could potentially regulate tumor vessel function to control tumor malignancy and response to therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA125255-06A1
Application #
8761755
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2008-07-10
Project End
2018-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$438,750
Indirect Cost
$213,750
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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