Researchers from The University of Texas Southwestern Medical Center have shown that an antibody targeting endotrophin, a fat cell-derived extracellular protein, reduced growth of breast tumors in mice.1 The team will next study the antibody in animal models of obesity-induced cancer and test a humanized version in human cancer samples.

Over the past decade, multiple epidemiological studies have shown a strong correlation between obesity, as measured by body mass index (BMI), and incidence of various solid and hematological cancers.2-4 Moreover, animal studies have shown that adipocytes in the tumor microenvironment secrete a variety of extracellular factors, some of which influence tumor development and progression.5

The ongoing challenge has been to determine which of those factors are most important in driving tumor growth and figuring out how to target them.

Philipp Scherer and Jiyoung Park at the UT Southwestern Medical Center have focused their efforts on the potential role of collagen type VI (COL6) in tumorigenesis. COL6 is a multimeric glycoprotein composed of three subunits: COL6 a1 (COL6A1), COL6A2 and COL6A3.

Scherer is professor of internal medicine and director of the Touchstone Diabetes Center and Park is assistant instructor of internal medicine at the UT Southwestern Medical Center.

Adipose tissue is the most abundant source of COL6,6 and research by multiple labs has shown that the target can mediate cell-cell signaling events and is upregulated in some tumor stroma.7,8

In two prior mouse studies, the UT Southwestern team found that Col6 promoted tumorigenesis and Col6 knockout reduced rates of early hyperplasia and primary tumor growth.9,10 They also found that endotrophin-an extracellular cleavage product of the Col6a3 subunit-was highly enriched in murine and human breast cancer samples.

Based on those findings, the researchers hypothesized that endotrophin could be the portion of COL6 responsible for promoting tumor growth and that blocking the protein might have an antitumor effect. They also suspected that targeting endotrophin might be safer than targeting the entire COL6 protein, which is required for the mechanical stability of many connective tissues including blood vessels, lung, muscle and skin.

The researchers first generated transgenic mice that expressed high levels of endotrophin in the mammary gland and then crossed those animals with mice that had aggressive mammary adenocarcinoma and pulmonary metastasis.

The resulting animals showed greater tumor volume and metastatic burden than mouse models with normal endotrophin expression, suggesting endotrophin enhanced both primary tumor growth and metastatic disease.

Subsequent experiments suggested a mechanism whereby endotrophin acted on both cancer cells and stromal cells to generate its effects. In cancer cells, endotrophin induced epithelial-mesenchymal transition, which led to increased metastases compared with no endotrophin. In the tumor stroma, endotrophin recruited and activated macrophages and endothelial cells, which in turn promoted tumor growth through increased angiogenesis (see "Targeting endotrophin in breast cancer").

To test the effects of directly blocking endotrophin, the researchers implanted wild-type mice with primary mammary epithelial cancer cells expressing high levels of the protein and treated them with an antiendotrophin antibody.

The animals had significantly lower tumor burden than mice given a control antibody (p<0.05). Histological analysis of tumor tissue showed decreased levels of stromal cell infiltration in mice receiving the antibody, confirming that endotrophin acted at least partly through stromal cells to trigger its tumorigenic effects.

The findings were published in The Journal of Clinical Investigation.

The paper "is a very significant advance and makes a contribution to explaining the mechanism of how adipocytes promote tumor growth," said Ernst Lengyel, professor of gynecologic oncology at The University of Chicago Pritzker School of Medicine.

In 2011, Lengyel and colleagues published in Nature Medicine that ovarian cancer cells used adipocyte-derived lipids for tumor growth in vitro and in mice.11

"Both the new JCI paper and our study show that adipocytes are not quiet, fat-containing cells but a very active and underappreciated component of the microenvironment which promotes tumor growth," said Lengyel.

Fattening up

Blocking endotrophin secreted by adipose tissue could be combined with approaches that target other adipocyte-derived factors to prevent tumorigenesis, said Jian-Wei Gu, assistant professor of physiology and biophysics at The University of Mississippi Medical Center.

In 2011, Gu and colleagues published data in Cancer Biology & Therapy showing that postmenopausal obesity in mice increased breast tumor weight compared with that in nonobese controls. The obese mice also had substantially higher levels of Vegf in the serum and visceral fat, suggesting adipose tissue expressed high levels of VEGF, which promoted tumor growth.12

Based on those findings, Gu said he is now testing anti-VEGF therapies in mouse models of postmenopausal obesity-associated breast cancer.

Corresponding author Scherer told SciBX his team will next study the antiendotrophin mAb in additional mouse models of obesity-associated malignancies, initially focusing on breast and colon cancers. "We also plan to humanize the antibody and test it in human breast and colon cancer samples," he said.

The JCI findings are not patented, Scherer said.

Fulmer, T. SciBX 5(41); doi:10.1038/scibx.2012.1071
Published online Oct. 18, 2012


1.   Park, J. & Scherer, P.E. J. Clin. Invest.; published online Oct. 8, 2012; doi:10.1172/JCI63930
Contact: Philipp E. Scherer, The University of Texas Southwestern Medical Center, Dallas, Texas

2.   Calle, E.E. & Kaaks, R. Nat. Rev. Cancer 4, 579-591 (2004)

3.   Renehan, A.G. et al. Lancet 371, 569-578 (2008)

4.   Calle, E.E. et al. N. Eng. J. Med. 348, 1625-1638 (2003)

5.   Park, J. et al. Endocrine Rev. 32, 550-570 (2011)

6.   Scherer, P.E. et al. Nat. Biotechnol. 16, 581-586 (1998)

7.   Berking, C. et al. Cancer. Res. 61, 8306-8316 (2001)

8.   St. Croix, B. et al. Science 289, 1197-1202 (2000)

9.   Iyengar, P. et al. Oncogene 22, 6408-6423 (2003)

10. Iyengar, P. et al. J. Clin. Invest. 115, 1163-1176 (2005)

11. Nieman, K.M. et al. Nat. Med. 17, 1498-1503 (2011)

12. Gu, J.-W. et al. Cancer Biol. Ther. 11, 910-917 (2011)


The University of Chicago Pritzker School of Medicine, Chicago, Ill.

The University of Mississippi Medical Center, Jackson, Miss.

The University of Texas Southwestern Medical Center, Dallas, Texas