Tumor-associated macrophages promote progression to malignancy, metastasis, and resistance to chemotherapy in breast and pancreatic cancer. Furthermore, the level of macrophages in patient tumors correlates with a worse prognosis in breast cancer. The phenotype of tumor associated macrophages is influenced by a plethora of inputs, including the cytokine milieu within the tumor. We have identified a population of macrophages in genetic models of breast and pancreatic adenocarcinoma that express Vascular Endothelial Growth Factor Receptor 2 (Vegfr2). Using flow cytometry and immunohistochemical analyses, we found that this population is enriched for markers associated with macrophages that promote angiogenesis, immune suppression, and metastasis. In vitro, we identified the heparin-binding peptide, pleiotrophin (PTN), as a candidate cytokine that induces Vegfr2 and anti-inflammatory cytokine expression by macrophages. Additionally, we found that PTN-stimulated macrophages greatly increase cancer cell migration in vitro. In the MMTV-PyMT transgenic murine model of breast cancer, we observed that tumor PTN expression correlates with levels of Vegfr2+ macrophages and progression to malignancy. Crizotinib, an inhibitor of the pleiotrophin receptor, Anaplastic Lymphoma Kinase, reduced anti-inflammatory and Vegfr2+ macrophages in vivo. This decrease was concomitant with a significant reduction in tumor angiogenesis and pulmonary metastasis. From our preliminary data, we hypothesize that Vegfr2+ macrophages promote progression to malignancy and metastasis.
Specific aims of this work are focused on identifying the function of PTN-stimulated macrophages in the tumor microenvironment, evaluating the efficacy of targeted anti-PTN therapy in preclinical models of breast cancer, and determining if macrophage Vegfr2 expression is required for tumor progression and metastasis. The potential impact of this work includes identifying a novel biomarker of pro-malignant macrophages, a therapeutic strategy to target them, and developing a deeper understanding of the function of macrophages in metastasis.

Public Health Relevance

The goal of this proposal is to understand the function and mechanism of pleiotrophin (PTN) signaling on tumor-associated macrophage phenotype. Tumor-associated macrophages support tumorigenesis and metastasis, and are associated with resistance to chemotherapeutics in breast cancer. We have previously demonstrated that PTN induces expression of anti-inflammatory markers and Vegfr2 on macrophages in vitro. Furthermore, PTN stimulated macrophages greatly increased tumor cell migration in vitro. Crizotinib, an inhibitor of the pleiotrophin receptor, anaplastic lymphoma kinase, curbed PTN's effects in vitro. Crizotinib also reduced tumor- associated Vegfr2+ and anti-inflammatory macrophages, as well as metastatic burden in the MMTV-PyMT transgenic model of breast cancer. Understanding the biology of the PTN/Vegfr2 signaling axis and intratumoral functional significance will give insight into the regulation of tumor-associated macrophage phenotype. This understanding will support therapeutic avenues targeting tumor-associated macrophages.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Schmidt, Michael K
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University of Texas Sw Medical Center Dallas
Schools of Medicine
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Sorrelle, Noah; Dominguez, Adrian T A; Brekken, Rolf A (2017) From top to bottom: midkine and pleiotrophin as emerging players in immune regulation. J Leukoc Biol 102:277-286