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Colorectal tumours initiate VEGF-A/CXCL1 cascade, creating distant niches for metastases

Primary colorectal tumours secrete VEGF-A, inducing CXCL1 and CXCR2-positive myeloid-derived suppressor cell (MDSC) recruitment at distant sites and establishing niches for future metastases, report Medical University of South Carolina (MUSC) investigators in an article published online by Cancer Research.

Liver-infiltrating MDSCs help bypass immune responses and facilitate tumour cell survival in the new location.

This research illuminates mechanisms by which primary tumours contribute to premetastatic niche formation and suggests CXCR2 antagonists may reduce metastasis.

Recent cancer research shows that premetastatic 'niches' form at sites far from the original tumour before new tumours occur.

In colorectal cancer (CRC), these supportive microenvironments form in preferred secondary organs, such as the liver and lung, and facilitate the colonisation, survival, and growth of metastasising tumour cells.

However, the mechanisms responsible for the formation of these premetastatic 'niches,' including what role(s) the primary tumour may play, are not well understood.

It is critical to better understand the mechanics of CRC metastasis, as it is the second leading cause of cancer deaths in the US and patients with advanced cases often die because current treatments for widely metastasised disease are not effective.

MUSC investigators led by Raymond N. DuBois, M.D., Ph.D., dean of the MUSC College of Medicine and professor of Biochemistry and Molecular Biology, have now illuminated how primary CRC tumours contribute to premetastatic 'niche' formation.

"The idea that some sort of 'priming' needs to take place for metastasis to occur in distant organs - that there is some sort of activity in the future tumour location - is not new. But most research has focused on growth factors, chemokines and pro-inflammatory cytokines. There hasn't been much work looking at immune cell activity in distant organs prior to metastasis," explains DuBois. "We knew that the type and density of immune cells in the primary tumour plays a role in progression. For example, when more immature myeloid cells are present in the tumour, it becomes resistant to immune attack. But we didn't know what to expect in a metastatic model."

To explore this area, the team first evaluated whether the presence of a primary tumour affected immune cell profiles in premetastatic liver and lung tissues of mice.

They found that the presence of a primary cecal tumour caused MDSCs to begin infiltrating the liver before metastasis began.

Working backward from this finding, they used a series of experiments to reveal the chain of events that led up to MDSC infiltration.

Because CXCR2 is essential for drawing MDSCs out of the bloodstream and toward CRC tumours and colonic mucosa, the team began looking for CXCR2 and its ligands (CXCL1, CXCL2, and CXCL5) in mouse liver tissue.

The team not only found that the ligand, CXCL1, attracted MDSCs from the bloodstream into premetastatic liver tissue, but also that administering a CXCR2 antagonist inhibited CXCL1 chemotaxis.

This demonstrated that CXCR2 is required for CXCL1 to induce MDSC liver infiltration.

In other words, the CXCL1-CXCR2 axis is required to recruit MDSCs to the liver.

Importantly, they also found that liver- infiltrating MDSCs secrete factors that promote cancer cell survival and metastatic tumour formation without invoking the innate and adaptive immune responses.

Next, because VEGF is known to induce CXCL1 expression in lung cancer, the research team examined whether VEGF secreted by CRC tumours also regulated CXCL1 expression.

Their results demonstrated that VEGF-A secretion by primary CRC tumour cells stimulates macrophages to produce CXCL1.

Interestingly, although VEGF-A knockdown inhibited liver metastasis, it did not affect the growth of the primary tumour.

"We did not expect to find that a primary tumour could affect a distant organ before any of the cancer cells arrived on site," says DuBois. "We were surprised to see these changes before a single metastatic cell took up residence."

Together, these studies reveal that VEGF-A secreted by the primary CRC tumour stimulates macrophages to produce CXCR1, which recruits CXCR2-expressing MDSCs from the bloodstream into healthy liver tissue.

The MDSCs then create a premetastatic 'niche' or micro-environment where cancer cells can grow to form new tumours.

These results demonstrate for the first time that cells in the primary tumour contribute to forming distant pre-metastatic 'niches' which facilitate the spread of disease.

"Now that we know the primary tumour puts things in motion remotely prior to metastasis, we should be able to inhibit this process and have a positive impact on survival," explains DuBois. "We now know which molecules and immune cells are involved and that if we disrupt the CXCL1-CXCR2 axis we can possibly reduce the spread of disease. Both antibodies and small molecules can inhibit this pathway, but they have not yet been optimised. I hope these findings will speed up the development of inhibitors of the CXCR2 pathway."

Source: Medical University Of South Carolina

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