Abstract PL03-01: Macrophage diversity promotes tumor progression and metastasis

Abstract

Abstract The tumor microenvironment represents a complex and changing ecology of many different cell types whose interactions determines the overall malignancy of the tumor. This environment consists of tumor cells harboring oncogenic and tumor suppressor mutations together with normal cells that include resident ones and those recruited from the bone marrow. In this latter class myeloid cells and especially macrophages, the subject of our studies, are particularly well represented. Associative clinical studies have indicated that the abundance of macrophages or overexpression of their signaling pathways is often an indicator of poor prognosis in a wide variety of cancers. These data suggests a pro-tumoral role for tumor-associated macrophages. This hypothesis that macrophages promoted malignancy is supported by a significant number of studies using genetic or pharmacological ablation of macrophages or their signaling pathways. In our studies, we used genetic ablation of macrophages in the model of breast cancer caused by the mammary epithelial expression of the Polyoma Middle T oncoprotein (PyMT). This ablation resulted in a slowing of tumor progression to malignancy and an inhibition of metastasis. We and our collaborators have identified several traits that macrophages confer in the primary tumor that account for their enhancement of malignancy. These are in the promotion of angiogenesis, stimulation of tumor cell invasion, migration and intravasation. At the metastatic site we have also shown that macrophages promote tumor cell extravasation and subsequent growth. Macrophage isolation and characterization from PyMT tumors and their metastatic sites suggest that each of these activities is regulated by a distinct subsets of macrophages that nevertheless express canonical macrophage markers. Each of these macrophage populations have defining cell surface markers and unique transcriptional profiles that suggest individual functions (Condeelis and Pollard, 2006; Qian and Pollard, 2010). Metastasis is the major cause of the failure of therapy and therefore death in cancer patients. Therefore we have focused our recent research on this process. We showed that macrophages are rapidly recruited to tumor cells as they metastasize to the lung. Ablation of these metastasis-associated macrophages (MAMs) using either genetic or pharmacological means results in an inhibition of tumor cell seeding and subsequent growth. Importantly ablation of these macrophages after the tumor cells have become established also inhibited subsequent metastatic growth suggesting that these cells represent therapeutic targets. Using ex vivo imaging methods we showed that a major action of these macrophages was on the promotion of tumor cell extravasation with subsequent effects on viability. This effect of macrophage on tumor cells could be recapitulated in an ex vivo extravasation assay thus enabling the interrogation of specific signaling molecules that may have function in promoting extravasation. To analyze the source of these MAMs, we performed adoptive transfers of the two different populations of monocytes that are defined by the presence or absence of the surface antigen Ly6C. Interestingly there was preferential recruitment of the Ly6C+ population to the metastatic sites whether in an experimental model of metastasis or into spontaneous metastases from PyMT tumors. Tracking of these monocytes showed that they rapidly differentiated into MAMs in the lung. A similar monocytic population (CD14+CD16-) circulating in human peripheral blood was recruited to human breast cancer metastases following adoptive transfer into immunocompromised mice. Furthermore, in mice we found that the Ly6C+ monocytes are preferentially recruited to bone metastases. In contrast to these data, Ly6C negative monocytes are recruited to the spontaneous tumors and to liver metastases there is a reduction in the recruitment of both populations of monocytes. Inhibition of the recruitment of these Ly6C+ monocytes inhibited tumor cell extravasation and thus metastases in bone and lung but not liver. These data suggest that alternative and tissue-specific mechanisms are operative at different metastatic sites. The dynamic acquisition of monocytic populations to primary and metastatic tumors and their differentiation into distinct macrophage populations represents the potential to target aspects of the tumor microenvironment. Such novel therapeutics in combination with conventional chemotherapeutic and/or radiation therapy may provide synergistic benefits to the patient. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL03-01. doi:10.1158/1538-7445.AM2011-PL03-01