What You Need to Know: The genes that favor staggered colon cancer metastasis have been discovered by researchers. Of the colon cancer patients that develop metastases, 40% develop metastasis first to the liver and later to the lung, always in this clinical order of appearance. The study reveals that the metastatic lesion in the liver is necessary for later metastasis to lung to occur, the former thus becoming a platform from which the cells prepare the subsequent lung metastatic niche to be colonized.
Without a previous lesion in the liver there is no lesion in the lung: Of colon cancer patients that develop metastases, 40% present metastasis first to the liver and later to the lung, always in this clinical order of appearance. Although this staggered behavioral pattern was known, it was not understood at the molecular level.
So What’s New? This study reveals that the metastatic lesion in the liver is necessary for later metastasis to lung to occur, the former thus becoming a platform from which the cells prepare the subsequent lung metastatic niche to be colonized. The researchers observed that established metastatic cells in the liver release a molecule called PTHLH. This molecule affects the cells of pulmonary blood vessels, which respond to PTHLH by triggering remodelling processes. When a tumor cells escapes from the liver to travel towards the lung, it releases more PTHLH, thus further stimulating the process. This causes the previously impermeable blood vessel walls to form gaps, which the metastatic cell exploits to cross into and colonize the lung.
“Without the signal from the liver, the tumour cells could hardly enter the lung. With PTHLH, the cells that have colonized the liver are armed with a system that facilitate their activity at a distant site and they are able to prepare a niche in which to generate a new lung lesion. The tumour cells gain capacity to form PTHLH when the levels of p38 MAPKinase are decreased,” explains Roger Gomis.
Of note, most patients that develop metastasis to the liver do not do so to the lung, thanks to maintenance — among other factors — of appropriate p38 MAPKinase levels. The experiments have been validated in 284 clinical samples from patients with stage II and III colon tumours. These are the most relevant cases clinically because they are patients that have not developed metastases but could have acquired this capacity. The results have also been confirmed in cell lines and mouse models.
I’m Dr. Michael Hunter.
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References: Jelena Urosevic, Xabier Garcia-Albéniz, Evarist Planet, Sebastián Real, María Virtudes Céspedes, Marc Guiu, Esther Fernandez, Anna Bellmunt, Sylwia Gawrzak, Milica Pavlovic, Ramon Mangues, Ignacio Dolado, Francisco M. Barriga, Cristina Nadal, Nancy Kemeny, Eduard Batlle, Angel R. Nebreda, Roger R. Gomis. Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nature Cell Biology, 2014; DOI: 10.1038/ncb2977; Institute for Research in Biomedicine-IRB. “Why colon cancer metastasis always follows the same invasive pattern.” ScienceDaily. ScienceDaily, 2 June 2014. <www.sciencedaily.com/releases/2014/06/140602101407.htm>.