Primary tumors spread by a process called metastasis, during which cells break off and move through the bloodstream to other parts of the body. Scientists initially thought that metastasis is mainly due to random genetic mutations acquired during the late stages of cancer progression. Jean-Pierre Abastado and colleagues at the A*STAR Singapore Immunology Network1 have now shown that immune cells derived from the bone marrow can infiltrate tumors and make them more aggressive.
The researchers noticed that metastasis occurs far earlier in the progression of the disease. They examined a strain of mutant mice which spontaneously develops eye tumors that metastasize and spread to the skin and lungs. The development of these secondary tumors normally takes more than six months.
They found that a subset of bone marrow-derived immune cells called myeloid-derived suppressor cells (MDSCs) gradually accumulate in primary tumors, and were five times more abundant in the primary than in the secondary tumors.
The researchers also found that primary tumors express 21 genes at levels that are at least two-fold higher than secondary tumors. Genes encoding small signaling molecules called chemokines were expressed at particularly high levels, with one, encoding the chemokine CXCL5, being expressed at a 56-fold higher level in primary than in skin tumors.
Analysis of the transcriptomes from the different types of tumor cells revealed that only MDSCs express CXCR2, a cell surface receptor for CXCL1, CXCL2, and CXCL5. In cell culture experiments, these three chemokines attracted MDSCs, and this attraction was blocked by compounds that inhibit CXCR2.
Further experiments revealed that MDSCs favor primary tumor growth by secreting soluble factors that promote the proliferation cancer cells, and that they also promote the spread of cancerous cells to other sites in the body.
They do so by promoting a process called epithelial–mesenchymal transition, which involves the loss of cell adhesion properties and is thought to be critical for promoting cancer cell spreading (see image). This occurs by activation of multiple signaling pathways.
Together, the findings show that MDSCs that infiltrate primary tumors can increase cancer cell aggressiveness by promoting their proliferation and dispersal, and that these changes occur much earlier in the development of the disease than previously thought.
“More than 90% of cancer-related death is due to metastasis,” says Abastado, “so a better understanding of the process is likely to help clinicians in improving disease control. We will determine whether our finding applies to human tumors and whether immune cells that favor cancer cell dissemination can be inhibited.”
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network
- Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biology 9, e1001162 (2011). | article