Control of Tumor Promotion and Metastatic Progression by Inflammatory Signaling

Michael Karin

Laboratory of Gene Regulation and Signal Transduction
Department of Pharmacology and Pathology
UCSD School of Medicine
La Jolla, CA 92093

There is ample epidemiological and mechanistic evidence that inflammation and inflammatory processes, such as these that lead to activation of NF-κB and STAT3, play a critical role in early tumor promotion and the growth and progression of primary tumors. Little information, however, exists regarding the role of inflammation in metastatic progression, which until recently was mainly attributed to genetic changes intrinsic to the cancer cell. Using a mouse model of prostate cancer metastatic progression, the TRAMP mouse, we found that activation and nuclear translocation of IkB kinase α (IKKα) within prostate cancer (CaP) cells is a critical event in metastatogenesis, as it is required for repression of the potent metastasis suppressor maspin. Activation of IKKα in CaP cells, however, depends on interaction with inflammatory cells that are recruited into the growing tumors and produce IKKα activating cytokines such as RANK ligand and lymphotoxin. Interestingly, expression of IKKα activating cytokines is dependent on IKKβ. Furthermore, androgen ablation therapy (such as castration) results in activation of IKKβ in immune cells that are recruited to the dying tumor and IKKα in the residual CaP cells that survive, leading to emergence of hormone-independent CaP.

To understand how inflammatory cells are recruited into growing tumors to promote metastatic progression, we screened carcinoma lines for their ability to produce soluble factors that activate macrophages and induce cytokine production. We identified one such factor as the extracellular matrix protein versican, whose expression is highly elevated in aggressive lung cancers, and have shown that it activates macrophages through TLR2 to produce TNF-α and other inflammatory cytokines. Most importantly, the ability of lung carcinoma cells that produce versican to establish metastatic growths is strongly dependent on TLR2 activation and TNF-α production by host bone-marrow derived cells.

These results strongly support the notion that metastatic progression is highly dependent on dynamic and reciprocal interactions between cancer cells and inflammatory cells, which are recruited into growing tumors to produce pro-metastatic cytokines.

Reference:

1. Karin, M., Cao Y., Greten, F., and Li, Z-W. (2002) NF-kB in Cancer: From innocent bystander to major culprit. Nature Rev Cancer 2:301-10.

2. Cao, Y., Bonizzi, G., Seagroves, T., Greten, F., Johnson, R., Schmidt, E., Karin, M. (2001) IKKa provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107:763-775.

3. Luo, J.-L., Tan, W., Ricono, J.M., Korchynskyi, O., Zhang, M., Gonias, S.L., Cheresh, D.A., Karin, M. (2007). Nuclear cytokine activated IKKa controls prostate cancer metastasis by repressing maspin. Nature 446: 690-4.

4. Kim, S., Takahashi, H., Lin, W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J., Karin, M. (2009) Carcinoma produced factors activate myeloid cells via TLR2 to stimulate metastasis. Nature 457, 102-6.

Last Reviewed
July 2018