Adipocyte-derived endotrophin promotes malignant tumor progression

Abstract

Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6α3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-β signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

“…Moreover, the ECM can serve as an endocrine organ due to the signalling potential of certain fragments released by proteolysis, creating ligands with paracrine and potential endocrine functions [3]. Endotrophin (Pro-C6) is a soluble fragment of the C-terminal α3 chain of type VI procollagen that is released by naturally occurring proteolysis [4,8,22,26]. Here we demonstrate that serum endotrophin levels are predictive of a response to the insulin sensitisers, pioglitazone and balaglitazone, in patients with type 2 diabetes.…”

“…In animal models, endotrophin levels have been shown to reflect insulin sensitivity, food intake and energy balance, as well as angiogenesis [4,5,8]. Accordingly, suppression of endotrophin improves insulin sensitivity and attenuated adipose tissue inflammation in animals [8].…”

“…The microflamentous interstitial type VI collagen, a triple helical molecule composed of the constituent chains α1(VI), α2(VI) and α3(VI), is expressed in most connective tissues and prominently in adipose tissue [4], where it anchors cells through its interconnections with other ECM proteins [5]. During formation of the microfilaments, the triple helical core of this type VI collagen is proteolytically released from its propeptide [6,7].…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…The marrows of these patients contain large numbers of adipocytes. Adipocytes are known to be involved in tumor progression and metastasis, 32,33 which may be partly owing to their negative effects on hematopoiesis; 13 however, little is known regarding the specific roles that these cells have in the metastatic process. A recent study demonstrated that marrow adipocytes support bone metastasis of prostate cancer, 34 as more PC3 cells, a prostate cancer cell line, grew in the bone marrow of animals receiving a high-fat diet than in that of animals on a regular diet.…”

Tissu adipeux et cancer

“…Une de ces protéines, qui est très exprimée par les adipocytes péritumoraux et qui favorise la croissance des tumeurs mammaires in vivo, est le collagène VI (Col6) [26]. Il a été récemment montré qu'un des fragments de clivage du collagène, l'endotrophine, agissait comme une molécule de signalisation et augmentait la fibrose, l'angiogenèse et l'inflammation dans le microenvironnement des tumeurs mammaires, favorisant ainsi l'agressivité tumorale et, en particulier, les métastases [27]. Les CAA expriment aussi la MMP11 (ou stromélysine 3), dont l'expression favorise la croissance des tumeurs mammaires [22].…”