COMMENTARY

The Genomics of Metastasis: Commandeering Host Immune Cells

Ali Torkamani, PhD

Disclosures

May 26, 2009

An elegant study investigating the interactions between cancer cells and the host immune system has revealed specific factors released by cancer cells that stimulate metastasis-promoting processes in host immune cells.[1] The in-depth study, led by Dr. Michael Karin's group at the University of California, San Diego, identified prometastatic inflammation induced by cancer cells; demonstrated that the inflammatory signal was secreted into the area surrounding tumor cells; identified the immune cell receptors required for response to the cancer-secreted signal; identified the specific inflammatory factors secreted by the cancer cells; verified a direct interaction between the identified factors and the host immune cell receptors; and demonstrated that removal of either this inflammatory signal or of the host immune cells' response to the inflammatory signal resulted in a decrease in the number and size of metastases to the lungs, liver, and adrenal glands of mice. Similarly, enhancing the secretion of the inflammatory signal in cancer cells that are not prone to metastasize resulted in an increase in the number and size of metastases.

Metastasis is the dissemination of tumor cells from the primary tumor to secondary sites throughout the body. According to the World Health Organization,[2] metastases are the leading cause of death from cancer. Metastasis depends on a wide range of intrinsic and extrinsic factors, including genetic and epigenetic alterations, interactions between tumor cells and primary tumors' surrounding environment, remodeling of the surrounding tumor environment, increases in tumor cell motility, homing to secondary sites throughout the body, and compatibility between tumor cells and environment of the secondary tumor site.[3]

It has been demonstrated that tumor cells interact with and, in many cases, recruit host cells during tumor progression and metastasis.[4] In particular, the removal of macrophages in mice has been shown to reduce the rate of tumor progression and nearly eliminate metastasis.[5] Similar results have been observed by eliminating key inflammatory mediators.[6] In human cancers, especially those originating in female-specific organs, increased expression of factors responsible for the growth and proliferation of macrophages has been associated with poor prognosis.[7] These observations suggest that macrophages are key players in the metastatic process, and may be directly recruited and activated by tumor cells.

In this light, Kim and colleagues[1] pursued a series of experiments in order to identify tumor-secreted factors that activate macrophages and promote metastasis. First, it was shown that inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, were more highly expressed in macrophages grown in media conditioned by tumor cells. This observation suggested that a factor secreted by tumor cells was able to activate the inflammatory response in macrophages. At the same time, increased survival and a decrease in the number and size of metastases was demonstrated in mice lacking TNF-alpha, suggesting that the inflammatory response promotes these processes.

A series of similar experiments in mice lacking a wide range of inflammatory receptors identified toll-like receptor 2 (TLR2), and its coreceptors TLR6 and CD14, as the macrophage receptors required for response to the cancer-secreted factor. Macrophages lacking TLR2 failed to show an inflammatory response when grown in cancer cell-conditioned media. Tracking tumor cells in vivo with fluorescent markers demonstrated that whereas tumor cells injected into the circulatory system of normal mice settled within the lungs, tumor cells failed to populate the lungs of mice lacking TLR2. In addition, tumor number and size were reduced in the lungs, liver, and adrenal glands of mice lacking TLR2. These effects were duplicated in normal mice lethally irradiated and reconstituted with bone marrow derived from TLR2 knockout mice.

Next, the specific factor mediating macrophage activation was identified by fractionating tumor cell-conditioned media and screening each fraction for the ability to activate inflammation in macrophages. The identity of the factor in each fraction capable of inducing macrophage inflammation was established by mass spectroscopy. The causative factor, versican, was verified by reducing its expression in metastatic cancer cells, or increasing its expression in nonmetastatic cancer cells, and observing parallel changes in mouse survival and tumor number and size. Finally, the direct interaction of versican with TLR2 was verified by co-immunoprecipitation of TLR2 and CD14 with a versican antibody.

These results suggest that cancer cells may specifically activate the host immune system in order to promote tumor metastasis. This leads to the counterintuitive proposal that suppression of the immune response may be an effective means of inhibiting tumor metastasis. It remains to be seen whether these findings will translate to oncologic practice someday or whether these activities are specific to the tumor cell lines studied. Nevertheless, the previous correlation between prognosis and the expression of macrophage proliferation factors in human tumors suggests that immunosuppressive therapies may, in fact, be relevant to human tumors.[7] Specifically disrupting the metastasis-promoting processes of the human immune system, while retaining important immune defense functions, may be the key to unlocking a new class of metastasis-suppressing therapies.

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