One of the most prominent characteristics of tumors is their abnormal vasculature. Constantly stimulated by angiogenic factors in the tumor environment, newly formed blood vessels fail to develop into a fully mature and functional vascular network. In recent years, we have begun to recognize the biological and clinical significance of the deficiency in maturation and the poor functionality of tumor blood vessels. Through improvement of the circulation within the tumor, normalization of such structurally and functionally abnormal tumor vasculature may significantly improve drug delivery and enhance the efficacy of conventional cytotoxic therapies. The long term goal of this study is, therefore, to understand the molecular mechanism of maturation and normalization of pathologically regenerating vasculature in the tumor. Our recent studies suggest that a small GTPase, R-Ras, promotes vessel maturation through induction of endothelial quiescence and facilitation of the formation of basement membrane and the sheath of pericytes enwrapping the nascent vessels. In this proposal, we will determine the role of R-Ras in regulating the maturation of tumor microvessels in vivo, analyze the cellular mechanism of this regulation in vitro, and determine the therapeutic significance of R-Ras-mediated vessel maturation in cancer using an R-Ras-null mouse model.
In Aim 1, we will investigate the effect of R-Ras deficiency on the structural and functional integrity of tumor microvessels in vivo.
In Aim 2, we will conduct in vitro analysis of the effect of R-Ras on endothelial cell activities related to the vessel maturation process (e.g. formation and stabilization of adherent junction to reduce vessel leakiness). We will also determine the role of R-Ras in pericyte regulation, including the role in endothelial-pericyte interaction, as this interaction is essential for the differentiation and functional maturation of both cell types.
In Aim 3, we will investigate how R-Ras affects the tumor progression and the therapeutic efficacies of cytotoxic treatments through promoting maturation of tumor vasculature. In this aim, we will also determine whether the normalization of tumor vasculature induced by antiangiogenic therapy and its clinical benefit are linked to the expression of R-Ras in the affected vessels. The findings from these studies could provide the rationale for design of effective cancer regimens.
Blood vessels develop abnormally in tumors. Due to this abnormality, malignant tumors lack adequate circulation, hindering the delivery of therapeutic agent to the tumors. This application proposes to investigate how we could manipulate the blood vessel network within the tumor in order to enhance tumor responses to chemotherapeutic or radiation treatments for cancer.
|Li, Fangfei; Sawada, Junko; Komatsu, Masanobu (2017) R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nat Commun 8:1720|
|Vähätupa, Maria; Prince, Stuart; Vataja, Suvi et al. (2016) Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy. Invest Ophthalmol Vis Sci 57:4898-4909|
|Zhao, Wei; Mazar, Joseph; Lee, Bongyong et al. (2016) The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes. J Invest Dermatol 136:819-28|
|Sawada, Junko; Li, Fangfei; Komatsu, Masanobu (2015) R-Ras Inhibits VEGF-Induced p38MAPK Activation and HSP27 Phosphorylation in Endothelial Cells. J Vasc Res 52:347-59|
|Yue, Xiling; Morales, Alma R; Githaiga, Grace W et al. (2015) RGD-conjugated two-photon absorbing near-IR emitting fluorescent probes for tumor vasculature imaging. Org Biomol Chem 13:10716-25|
|Sawada, Junko; Li, Fangfei; Komatsu, Masanobu (2015) R-Ras protein inhibits autophosphorylation of vascular endothelial growth factor receptor 2 in endothelial cells and suppresses receptor activation in tumor vasculature. J Biol Chem 290:8133-45|
|Toba, Michie; Alzoubi, Abdallah; O'Neill, Kealan et al. (2014) A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension. Am J Pathol 184:369-75|
|Yanez, Ciceron O; Morales, Alma R; Yue, Xiling et al. (2013) Deep vascular imaging in wounds by two-photon fluorescence microscopy. PLoS One 8:e67559|
|Tigges, Ulrich; Komatsu, Masanobu; Stallcup, William B (2013) Adventitial pericyte progenitor/mesenchymal stem cells participate in the restenotic response to arterial injury. J Vasc Res 50:134-44|
|Sawada, Junko; Urakami, Takeo; Li, Fangfei et al. (2012) Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels. Cancer Cell 22:235-49|
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