Endotrophin – Linking Obesity with Aggressive Tumor Growth

Commentary on: Adipocyte-derived endotrophin promotes malignant tumor progression Collagen VI (COL6, encoded by the COL6A1, COL6A2, and COL6A3 genes) is an extracellular matrix protein that forms a microfilamentous network in various connective tissues, including skeletal muscle, cartilage, skin and adipose tissue. Among the various tissues, adipose tissue is by far the most abundant source of COL6 microfilaments [1]. Clinically, mutations in COL6 develop mild muscle myopathies (such as Bethlem myopathy and Ullrich congenital muscular dystrophy), with symptoms of muscle weakness and apoptosis combined with joint hyperlaxity and contractures [2]. A genetically engineered mouse model, deficient in COL6 microfilament formation and secretion, has been widely used to investigate the roles of COL6 under physiological and pathological conditions. COL6 deficiency in mice leads to the development of muscle dystrophies resembling Bethlem myopathy in man [3]. In the area of tumor biology, COL6 has been identified as a tumor-promoting factor abundantly produced and released from adipocytes [4]. Subsequent analysis of the COL6 functional null mice bred into the murine MMTV-PyMT mammary tumor model (mouse mammary tumor virus-polyoma middle T antigen) showed a significant attenuation of early onset mammary tumor progression [5]. Specifically, the carboxyl-terminal domain of the COL6A3 chain is massively upregulated in the malignant tumors of human patients compared to the remaining part of COL6A3 chain [5]. We recently followed up on this phenomenon and demonstrated that the cleavage product from the carboxyl-terminus of the COL6A3 chain (that we refer to as endotrophin) accounts for the tumor-promoting effects associated with COL6 [6]. Ectopic expression of the isolated endotrophin fragment within the tumor microenvironment of MMTV-PyMT mice drives an increase of both primary tumor growth and pulmonary metastasis through an enhancement of the expansion of the tumor stroma [6]. Additional prominent effects associated with endotrophin overexpression in the tumor stroma include an increase in fibrosis, angiogenesis and inflammation through increased fibrogenesis, a stimulation of epithelial-mesenchymal transition (EMT) and chemokine activities; these are well-established stromal phenomena that support aggressive traits of tumors (Figure 1). Indeed, neutralizing monoclonal antibodies against endotrophin suppress tumor growth and reduce metastatic growth in MMTV-PyMT mice [6]. EMT of tumors conveys metastatic traits and multiple drug resistances to cancer cells. Since endotrophin is a potent stimulator of EMT, it suggests that the neutralization of endotrophin may lend itself to enhance chemo-sensitivity in combination with conventional therapeutic regimens, though this remains to be directly shown. Adipose tissue is a crucial organ …