Anti-VEGF Therapy Modulates Immune Cell Infiltration and Function in Multiple Breast Cancer Models

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Title: Anti-VEGF Therapy Modulates Immune Cell Infiltration and Function in Multiple Breast Cancer Models
Author: Lynn, Kristi Dawn
Abstract: Breast cancer is the most frequently diagnosed malignancy in women in North America . Advancements in standard treatment regimens have improved the overall outlook for breast cancer patients in recent years ; however , 40 ,000 women a year succumb to this disease . Breast cancer is initiated when mammary epithelial cells acquire mutations in genes that regulate cell proliferation , survival , polarity , and differentiation . However , a growing body of evidence indicates that the stromal cell response to these malignant cells participates in tumorigenesis and is required for the tumor to advance past the hyperplastic stage . Angiogenesis , or expansion of the existing vascular network , is required for the growth of solid tumors . For this reason , tumor angiogenesis is an attractive target for tumor therapy . Many of the current anti -angiogenic therapies target vascular endothelial growth factor -A (VEGF ) . VEGF binds to and activates two primary VEGF receptors , VEGFR1 and VEGFR2 . VEGFR2 is the primary angiogenic receptor , while the function of VEGFR1 is less defined . It is important to note that the VEGFRs are expressed on endothelial cells , tumor cells and on many host immune cells . Therefore , to better understand the biology of anti -VEGF therapy it is important to consider the effects of VEGF on all VEGFR -positive cells in the tumor microenvironment . In the present study , immune cell infiltration and function were analyzed following anti -VEGF therapy . Inhibition of VEGF :VEGFR2 signaling with r84 or mouse -chimeric (mcr84 ) decreases tumor -associated myeloid -derived suppressor cells and increases mature dendritic cells in multiple models of breast cancer . In contrast to other immunosuppressive cell types , an increase in anti -inflammatory macrophage infiltration was observed following treatment with mcr84 , corresponding to an increase in the cytokine pleiotrophin (PTN ) . Once expressed , PTN stimulates the phosphorylation of anaplastic lymphoma kinase on tumor associated macrophages . These macrophages promote anti -inflammation , angiogenesis , immune tolerance , and metastasis . Importantly , these phenomena can be inhibited using the receptor tyrosine kinase inhibitor crizotinib , Furthermore , the combination of mcr84 and crizotinib decreased metastatic burden in animals with already disseminated disease . These findings suggest that mcr84 is a valid clinical candidate in breast cancer and its combination with crizotinib has the potential to reduce metastastic burden in patients with already disseminated disease .
URI: http : / /hdl .handle .net /2152 .5 /948
Date: 2011-12-14


Anti-VEGF Therapy Modulates Immune Cell Infiltration and Function in Multiple Breast Cancer Models. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /948 .

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