It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.

Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumors 1,2 . To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage activating factors secreted by metastatic carcinomas. Amongst the cell lines screened, Lewis lung carcinoma (LLC) 3 were the most potent macrophage activators leading to production of IL-6 and TNF-α through activation of the Toll-like receptor family members 4 TLR2 and TLR6. Both TNF-α and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC conditional medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumors including lung cancer 5,6 , as a macrophage activator that acts via TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-α secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone marrow-derived myeloid progenitors 7 , to generate an inflammatory microenvironment hospitable for metastatic growth.Distant site metastases are the leading cause of cancer-associated mortality and depend on genetic and/or epigenetic alterations that are intrinsic to cancer cells or extrinsic factors provided by the tumor microenvironment 1 . For instance, cytokines produced by inflammatory cells can enhance metastatogenesis by repressing the metastasis suppressor maspin within primary prostate carcinoma cells 8 . Furthermore, tumor progression and metastasis positively correlate with presence of infiltrates containing myeloid and lymphoid cells 2,9 . It was shown that certain carcinomas secrete factors that upregulate fibronectin and recruit vascular endothelial growth factor receptor 1 (VEGFR1)-positive hematopoetic progenitors to sites of Correspondence and requests for materials should be addressed to M.K. future metastatic growth, termed the pre-metastatic niche 7 . To examine whether cancer cells secrete factors that directly activate myeloid cells to produce tumor promoting cytokines 10 , we collected serum free conditioned medium (CM) from different cancer cell lines, derived mainly from C57BL6 mice, and applied it to bone marrow (BM)-derived macrophages (BMDM), which were assayed for production of IL-1β, IL-6 and TNF-α. The screen included 1C1C7 and TrampC1, which are liver and prostate cancer cell lines, respectively, with little or no metastatic activity, and two metastatic breast and lung carcinomas, 4T1 and LLC, respectively. CM from metastatic cells, especially LLC, induced higher amounts of IL-6 and TNF-α secretion than CM from non-metastatic cells (Fig. 1A). IL-1β secretion was undetectable and the CM did not contain IL-6 or TNF-α (data not shown). LLC-CM (LCM) also induced expression of Il1β, Il6 and Tnfα mRNAs, whereas serum free medium (SFM) and NIH3T3 CM were inacti...

The antidiabetic drug metformin exerts chemopreventive and antineoplastic effects in many types of malignancies. However, the mechanisms responsible for metformin actions appear diverse and may differ in different types of cancer. Understanding the molecular and cellular mechanisms specific for different cancers is important to optimize strategy for metformin treatment in different cancer types. Here, we investigate the in vitro and in vivo effects of metformin on esophageal squamous cell carcinoma (ESCC) cells. Metformin selectively inhibited cell growth in ESCC tumor cells but not immortalized noncancerous esophageal epithelial cells. In addition to apoptosis, metformin triggered autophagy. Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream target Bcl-2 was inactivated by metformin treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability. Similarly, the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy, was repressed by metformin. Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis. In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth. Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy.

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