Switch-Hitting Immune Cells: From Tumor Protection to Metastasis Promotion

Myeloid cells (blue) produced in tumor-bearing mice are present prior to tumor cell (gold) arrival in the lung. The myeloid cells produce various factors that alter the pre-metastatic lung environment making it easier for tumor cells to exit blood vessels and to colonize the lung.

Myeloid cells (blue) produced in tumor-bearing mice are present prior to tumor cell (gold) arrival in the lung. The myeloid cells produce various factors that alter the pre-metastatic lung environment making it easier for tumor cells to exit blood vessels and to colonize the lung.

The leading cause of death from cancer is not a primary tumor but is the metastases, or invasion of tumor cells into other locations in the body, that result from it. A complex and incompletely understood process, metastatic tumor formation is thought to require several steps in which tumor cells invade the tissue surrounding the primary tumor, enter local blood vessels, navigate the circulation, exit the vasculature, and colonize a new site. Tumor cells do not, however, operate independently, and the role that the immune system plays in this metastatic process is beginning to be appreciated.

Initially, immune cells target and eliminate tumor cells by detecting the expression of altered cell surface or secreted proteins. This can select for tumorigenic cells without an altered protein profile capable of escaping immune detection. Once a tumor has formed, immune cells can produce immunosuppressive signaling molecules or activate inhibitory immune cells that further cloak the tumor. It is currently unclear, however, whether cells of the immune system can actually direct the formation of metastases.

Hannah Yan, a graduate student working with Li Yang, Ph.D. in the Laboratory of Cancer Biology and Genetics, and their colleagues were interested in understanding how immune cells influence a distant organ before tumor cell arrival, which is known as the pre-metastatic site. Using mice with an intact immune system, the scientists injected breast cancer cells and monitored their metastasis to the lung, a prominent metastatic site in breast cancer patients. Their results were recently published in the journal Cancer Research.

The researchers first examined the cell types found in the lung. Lungs from the tumor-bearing mice showed an increased level of a myeloid (immune) cell type. Importantly, the myeloid cells arrived at the lung at least seven days before any detectable breast cancer cells, suggesting that these myeloid cells may be critical for metastasis to this site.

The scientists then measured the levels of a variety of cell-signaling molecules. The lungs of the tumor-bearing mice showed much lower levels of a key anti-tumor immune stimulant, likely due to a decrease in the number of lung macrophages, a cancer-fighting immune cell type. The researchers also saw increased immune suppressive, inflammatory, and proliferative signaling molecules in the tumor-bearing mouse lungs, which could promote tumor cell growth and survival. These results indicate that the presence of the myeloid cells correlates with an increased hospitality for potential metastatic tumor cells in the lungs of cancer-bearing mice.

The most potently increased protein in the lungs of the cancer cell injected animals, prior to tumor cell arrival, was MMP-9, a protease previously implicated in tumor progression. MMP-9 expression in the lung co-localized with the myeloid cells, and the levels of MMP-9 activity in the whole lung and in myeloid cells isolated from the lung were approximately equal, suggesting that the MMP-9 activity in the lungs of the injected animals came from the myeloid cells. This data further supports the idea that the myeloid cells are responsible for stimulating changes in the pre-metastatic lung environment.

One of these important environmental factors is the vasculature that supplies the lung and serves as a barrier for potential metastatic cells. Compared to untreated mice, the pre-metastatic lungs of tumor-bearing mice showed increased, disorganized vasculature, which was leakier than normal, suggesting that tumor cells could have increased access to the lung tissue. Indeed, additionally injected, fluorescently-labeled tumor cells accumulated more rapidly in the lungs of previously tumor-injected mice.

Since MMP-9 plays a role in tumor vascular remodeling and was significantly increased in the pre-metastatic lung, the scientists investigated whether MMP-9 expression was required for lung metastasis. Growing endothelial cells, which line blood vessels, with myeloid cells from wild type mice caused a decrease in cell-to-cell contacts between the endothelial cells, analogous to increased leakiness in a blood vessel. In contrast, growing the endothelial cells with myeloid cells lacking MMP-9 caused no change in cell junctions. Likewise, when MMP-9 knock-out animals were injected with breast cancer cells, fewer disruptions in lung vasculature were observed and very few lung metastases formed, even though primary tumor growth was unchanged.

These studies support the idea that a type of cancer-induced immune cell promotes tumor metastasis by making the pre-metastatic tissue environment hospitable to tumor cells. Here, the tumor-stimulated myeloid cells over-expressed the vascular remodeling MMP-9 protease easing tumor cell access to the lung. Additionally, the presence of the myeloid cells correlated with changes in lung tissue expression, increasing the likelihood of metastatic tumor growth by promoting an immune suppressive, inflammatory, and proliferative environment. Future studies addressing methods to block metastasis-promoting immune cells will be important for improving the survival of cancer patients.

Summary Posted: Wed, 09/01/2010


Cancer Res. 2010 Aug 1;70(15):6139-49 PubMed Link