Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy whose growth, like that of all solid cancers, is dependent on neovascularization. The mechanism by which tumors induce a neovascular response is considered to be through angiogenesis: the process of new blood vessel formation from pre-existing ones. However, new blood vessels can also form through vasculogenesis, in which vessels from de novo by the assembly of precursor cells, including CD34 positive hematopoietic progenitor cells. Past work by the investigator had shown that HNSCC tumor cells mobilize CD34 positive hematopoietic progenitor cells, leading to increased levels of these cells in the periphery and within the tumor mass. They hypothesize that HNSCC stimulate neovascularization not only by angiogenesis, but also by vasculogenesis through the chemoattraction of CD34 positive cells and the induction of their differentiation into endothelial cells that become incorporated into the newly formed vasculature of the tumor. This hypothesis will be tested in vitro with primary HNSCC cultures and CD34+ progenitor cells isolated from blood of HNSCC patients and umbilical cords, and in vivo in a human HNSCC xenogeneic model through the following specific aims: To identify the HNSCC-derived factors that chemoattract CD34 positive progenitor cells (Aim 1) and induce their differentiation into endothelial cells (Aim 2). To determine in vivo if tumors attract CD34 positive progenitor cells as well as induce their differentiation into endothelial cells of the newly formed tumor vasculature (Aim 3). These studies will also determine if blocking the CD34+ cell chemoattraction or diversion to endothelial cell differentiation can block HNSCC-induced vasculogenesis. The proposed studies are expected to show that vasculogenesis contributes to tumor neovascularization. In addition, these studies may provide insights into therapies that can block tumor-induced vasculogenesis which, when included with strategies to block angiogenesis, can result in a more comprehensive therapeutic approach to blocking tumor vascularization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085266-02
Application #
6377599
Study Section
Special Emphasis Panel (ZRG1-ET-1 (01))
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2001-05-09
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$198,450
Indirect Cost
Name
Loyola University Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Mulligan, Jennifer Konopa; Young, M Rita I (2010) Tumors induce the formation of suppressor endothelial cells in vivo. Cancer Immunol Immunother 59:267-77
Mailloux, Adam W; Clark, Anna-Maria A; Young, M Rita I (2010) NK depletion results in increased CCL22 secretion and Treg levels in Lewis lung carcinoma via the accumulation of CCL22-secreting CD11b+CD11c+ cells. Int J Cancer 127:2598-611
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Mulligan, Jennifer K; Lathers, Deanne M R; Young, M Rita I (2008) Tumors skew endothelial cells to disrupt NK cell, T-cell and macrophage functions. Cancer Immunol Immunother 57:951-61
Walsh, Jarrett E; Lathers, Deanne M R; Chi, Angela C et al. (2007) Mechanisms of tumor growth and metastasis in head and neck squamous cell carcinoma. Curr Treat Options Oncol 8:227-38

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