Abstract 4940: Perivascular macrophages induce localized, transient blood vessel permeability and tumor cell intravasation

Abstract

Abstract Metastasis is a multistep process involving tumor and stromal cells. The microanatomical site consisting of a perivascular macrophage interacting with a Mena over-expressing tumor cell has been named the “tumor microenvironment of metastasis” (TMEM). TMEM density predicts distant metastatic recurrence in breast cancer patients making the study of TMEM function essential. In spontaneous orthotopic mouse mammary tumors (MMTV-PyMT), as the tumor progresses to malignancy tumor cells have increased Mena expression and assemble TMEM. TMEM assembly is correlated with elevated levels of circulating tumor cells and lung metastases, indicating a functional role for TMEM in tumor cell dissemination. High-resolution multiphoton-based microscopy at single cell resolution has revealed transient blood vessel permeability events at TMEM, marked by the extravasation of otherwise impermeable serum markers such as Qdots and fluorescent 155 kDa dextran. In proximity to sites of permeability there is increased tumor cell and macrophage motility towards the blood vessel, and local intravasation of tumor cells. Blocking macrophage function results in decreased blood vessel permeability and decreased numbers of circulating tumor cells. TMEM-associated macrophages produce VEGF-A, and blocking VEGF-A reduces blood vessel permeability and circulating tumor cells. The observation that TMEM mediates tumor cell intravasation through localized blood vessel permeability in live animals demonstrates that TMEM is a key metastatic microenvironment in the primary tumor, explains the prognostic value of TMEM density in predicting distant metastatic recurrence in breast cancer patients and suggests a potentially valuable re-tasking of existing anti-angiogenesis drugs. This research is supported by the Department of Defense [Breast Cancer Research Program)] under award number BC120227 (ASH). Note: This abstract was not presented at the meeting. Citation Format: Allison S. Harney, Esther N. Arwert, David Entenberg, Yarong Wang, Joan G. Jones, John S. Condeelis. Perivascular macrophages induce localized, transient blood vessel permeability and tumor cell intravasation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4940. doi:10.1158/1538-7445.AM2014-4940