Editors' ChoiceCancer

The fat of the (cancer) matter

Sci. Signal.  16 Aug 2016:
Vol. 9, Issue 441, pp. ec186
DOI: 10.1126/scisignal.aai7951

We have an increasing understanding of how cells in the tumor microenvironment and metastatic niche contribute to cancer. Likewise, it is clear that obesity is linked with cancer. Two studies now show how adipocytes secrete factors that promote tumor progression. In pancreatic ductal adenocarcinoma (PDAC) patients, obesity, inflammation, and fibrosis are associated with disease progression and poor clinical outcome. Incio et al. found that PDAC-associated adipocytes stimulate a feed-forward, proinflammatory loop in the tumor microenvironment by secreting the cytokine interleukin-1β (IL-1β). In mouse models of PDAC, obese mice had an increased abundance of IL-1β in adipocyte-rich tumor regions, tumor infiltration of neutrophils, and activation of angiotensin-1 (AT1) in pancreatic stellate cells, which remodel the extracellular matrix to produce the classic fibrotic desmoplasia associated with PDAC. Depleting tumor-associated neutrophils and neutralizing IL-1β with antibodies decreased the abundance of AT1 and fibrotic markers in the PDAC microenvironment and decreased tumor growth in obese mice. Neutralizing IL-1β alone decreased the infiltration of neutrophils, but neutrophil depletion alone also decreased the abundance of IL-1β in tumors, suggesting a multicellular and autocrine-paracrine feedback loop of inflammation and fibrosis driven by IL-1β. PDACs in obese mice also had impaired uptake of chemotherapeutics, as is often seen in patients. Deleting the gene encoding AT1 or treating mice with the clinically available AT1 inhibitor losartan decreased the abundance of fibrotic markers and increased the efficacy of chemotherapeutics such that the combination induced tumor regression.

In patients with serous ovarian cancer, the adipocyte-rich omentum, the tissue that covers the intestine, is a metastatic niche. Salt-inducible kinase 2 (SIK2) is a kinase that regulates lipid metabolism and promotes proliferation in ovarian cancer cells. Using patient tumor tissues and various experiments involving cell line cocultures and xenograft models in mice, Miranda et al. found that adipocytes stimulated the activity of SIK2 in serous ovarian cancer cells. Adipocytes secrete free fatty acids (FFAs), including oleic acid. Application of oleic acid (isolated from human omental adipocytes) dose-dependently stimulated an increase in intracellular Ca2+ in cultured ovarian cancer cells, which consequently led to autophosphorylation of SIK2, phosphorylation of the kinase AKT, and proliferation, similar to the effects seen in cells cocultured with isolated adipocytes. In vitro assays revealed that SIK2 phosphorylated the p85α subunit of PI3K, specifically at the Ser154 and Ser541 residues. Calcium chelators, an inhibitor of the endoplasmic reticulum calcium uptake pump, or an inhibitor of the kinase PI3K prevented the adipocyte coculture–induced proliferative effects in ovarian cancer cells. Injecting orthotopic xenograft-bearing mice with nanoliposomes carrying small interfering RNA against SIK2 decreased the frequency and size of abdominal metastases. Thus, these studies identified how an accumulation of adipocytes in the tumor microenvironment can stimulate tumor or metastatic growth, potentially revealing new targets for therapeutic intervention.

J. Incio, H. Liu, P. Suboj, S. M. Chin, I. X. Chen, M. Pinter, M. R. Ng, H. T. Nia, J. Grahovac, S. Kao, S. Babykutty, Y. Huang, K. Jung, N. N. Rahbari, X. Han, V. P. Chauhan, J. D. Martin, J. Kahn, P. Huang, V. Desphande, J. Michaelson, T. P. Michelakos, C. R. Ferrone, R. Soares, Y. Boucher, D. Fukumura, R. K. Jain, Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 6, 852–869 (2016). [PubMed]

F. Miranda, D. Mannion, S. Liu, Y. Zheng, L. S. Mangala, C. Redondo, S. Herrero-Gonzalez, R. Xu, C. Taylor, D. Fotso Chedom, M. Karaminejadranjbar, A. Albukhari, D. Jiang, S. Pradeep, C. Rodriguez-Aguayo, G. Lopez-Berestein, E. Salah, K. R. Abdul Azeez, J. M. Elkins, L. Campo, K. A. Myers, D. Klotz, S. Bivona, S. Dhar, R. C. Bast Jr., H. Saya, H. G. Choi, N. S. Gray, R. Fischer, B. M. Kessler, C. Yau, A. K. Sood, T. Motohara, S. Knapp, A. A. Ahmed, Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche. Cancer Cell 30, 273–289 (2016). [PubMed]