RESEARCH HIGHLIGHTS
Cancer biology Cause of dissemination Invading immune cells promote the growth and spread of primary tumors
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 col- leagues 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 accu- mulate 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 second- ary 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 pro- liferation 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–mes-
enchymal 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 sig- naling pathways. Together, the findings show that MDSCs that infiltrate primary tumors can increase cancer cell aggressiveness
A*STAR RESEARCH OCTOBER 2011– MARCH 2012
EGF
Primary Tumor
TGF-β HGF
CXCL1 CXCL2
CXCL5
Secretions Migration Tumor Cell PMN-MDSC
Local Metastasis
Distant Metastasis
Myeloid-derived suppressor cells (MDSCs) promote metasasis of primary tumors by activating multiple signaling pathways
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 metas-
tasis, so a better understanding of the process is likely to help clinicians in improving disease control,” says Abastado. “We will determine whether our finding applies to human tumors and whether immune cells that favor cancer cell dissemination can be inhibited.”
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1. 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).
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