Abstract IA7: Cachexia, immune suppression, and the FAP+ stromal cell.

Abstract

A membrane protein, fibroblast activation protein-alpha (FAP), identifies a mesenchymal stromal cell type that is present in almost all human adenocarcinomas. A recent report (Kraman, et al. Science 2010) showed that its conditional depletion in a mouse ectopic tumor model alleviated the immune suppressive block of the tumoral microenvironment, and allowed immune control of tumor growth. In addition to enhancing the understanding of how cancers escape immunosurveillance, this finding suggested that depleting FAP+ stromal cell represents a tumor immunotherapeutic approach. A prerequisite to such an approach, however, would be the demonstration that FAP+ stromal cells do not have essential functions in normal tissues and organs. We constructed a BAC transgenic mouse in which FAP+ cells would express both luciferase and primate diphtheria toxin receptor, which would permit bioluminescent imaging and conditional depletion of FAP+ cells, respectively. We have made the following observations with these mice. One, FAP+ stromal cells are widely distributed in almost all organs and tissues of the adult mouse. Two, depleting FAP+ cells by administration of diphtheria toxin to these mice causes two acute and striking changes: loss of skeletal muscle mass and cachexia, and a hypocellular bone marrow with arrest of erythropoiesis. Analysis of the genes expressed by FAP+ stromal cells in the skeletal muscle and bone marrow indicates that their loss from the former site leads to excessive signaling through the myocyte activin IIB receptor, leading to a hyercatabolic state in the myocyte, and from the latter site leads to deficiencies in KitL and Cxcl12, which are required to sustain normal hematopoiesis. Since cachexia and anemia are two of the frequent of the paraneoplastic syndromes, we looked for abnormalities of the FAP+ stromal cell in the skeletal muscle and bone marrow of mice bearing an ectopic C26 tumor, and the KPC model of spontaneous pancreatic ductal adenocarcinoma (PDA) that exhibited these paraneoplastic abnormalities. In both models, the number of FAP+ stromal cells in skeletal muscle and bone marrow were significantly decreased, causing deficiencies in these tissues of the essential proteins produced by these stromal cells. Therefore, the FAP+ stromal cell may contribute to the morbidity and mortality of cancer in two ways: accumulation within tumors to block immune control of tumor growth, and depletion from normal tissues to cause cachexia and anemia. Understanding the processes that control these processes affecting the FAP+ stromal cell has the potential for important new cancer therapies. Citation Format: Douglas T. Fearon, Edward Roberts. Cachexia, immune suppression, and the FAP+ stromal cell. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA7.