A Mechanism by which Chronic Inflammation Spurs Cancer Metastasis
Chronic inflammation is a risk factor for cancer and cancer mortality. There are numerous reasons as to why this might be the case, some much more proven and settled than others, but the research here is focused on metastasis, the spread of cancerous cells throughout the body. Since cancer mortality is largely determined by whether or not a tumor progresses to the point of metastasis, we should not be surprised that researchers can identify mechanisms linking inflammation with metastasis.
Dysregulated inflammation is recognized as one of the hallmarks of cancer and is involved in tumor initiation, progression, and metastasis. Chronic inflammatory conditions, such as chronic obstructive pulmonary disease or ulcerative colitis, are strongly associated with elevated cancer incidence. Chronic use of aspirin or other non-steroidal anti-inflammatory drugs reduces mortality of esophageal, colorectal, and lung cancers.
Thus chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in individuals at-risk for lung cancer, and in the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory.
Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory.
Although it is well known that EMT endows cells with metastatic capacity, analysis of tissue specimens from metastatic tumors often reveals cells with epithelial features. EMT plasticity therefore is proposed to temporally modify these properties by facilitating cellular responses to the microenvironmental stimuli that lead to mesenchymal phenotypes and metastatic behaviors. In the current study, fading of EMT memory, accompanied by a gradual elevation of E-cadherin expression, is consistent with a profound EMT plasticity. In a case of acquired EMT, increased migration and invasion of tumor cells enable them to travel away from primary tumor sites, which also distance them from EMT-promoting stimuli, such as inflammatory factors in the primary TME. We propose that because of the memorized EMT phenotypes, these migratory cells are able to seed the metastatic spread to distant organ sites.