Colorectal Cancer Small Extracellular Vesicles Induce Matrix Metalloproteinase Expression, an Invasion-Promoting Phenotype, and CD147-Dependent MAPK/AP-1 Activation in Macrophages

• Author / Creator

  Menghisteab, Isaac

• Exosomes and small microvesicles are types of small extracellular vesicle (sEVs) secreted by cancerous and normal cells. sEVs are filled with cargo from cancer cells that may affect both nearby and distant tissues. sEVs from colorectal cancers that enter blood vessels draining the intestine will traffic to the liver due to the normal blood flow path through the portal vein. Exosomes from colorectal cancers may induce changes in liver tissues by mechanisms such as the digestion of extracellular matrix (ECM) proteins. This creates sites known as premetastatic niches in the liver that are favorable to metastasis. Because Kupffer cells, which are tissue resident liver macrophages, and recruited inflammatory macrophages may be affected by colorectal cancer sEVs, we hypothesized that liver macrophages are conditioned by colorectal cancers sEVs to degrade the liver ECM through release of matrix metalloproteinases (MMP)s. We predict such ECM degradation by Kupffer cells may be one mechanism by which colorectal cancer sEVs help establish a premetastatic niche in the liver. Using in vitro and ex vivo models, we have found that sEVs from colon cancer cell lines directly induce invasion-promoting behaviours in liver macrophages that involve upregulating MMP production in a way that facilitates colorectal cancer cell migration,. These two consequences of sEV stimulation of macrophages occurs simultaneously with MAPK/AP-1 activation and is regulated in part by CD147 proteins on the colon cancer cell sEVs. These results confirm our hypothesis and support a role of colorectal cancer sEVs in preparing a liver pre-metastatic niche through conditioning liver macrophages.

• Subjects / Keywords

  • oncology
  • Kupffer cells
  • TAMs
  • cancer
  • exosomes
  • immunology
  • premetastatic niche
  • macrophages
  • metastasis
  • extracellular vesicles
  • MMPs
  • CD147

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-hs32-2560

• License

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