UBC Theses and Dissertations
The role of the microenvironment and inflammation in the promotion of cancer metastasis Arif, Arif A.
Circulating tumor cells become fully metastatic if they are able to extravasate from the microvasculature and move into microenvironmental niches within distant site organs where they survive and proliferate. To determine if inflammation facilitates this process, models of inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced injury were used, followed by introduction of B16F0 melanoma cells into the microvasculature of the lungs. Strikingly, all three conditions increased overt metastasis without increasing extravasation and the number and size of early metastases were increased. Bleomycin induced inflammation led to the increased survival of B16F0 tumor cells and recruitment of monocyte derived macrophages (MoDM) to the lungs. These MoDM were located near the micrometastatic niche and their presence correlated with increased metastatic tumor cell burden. Inflammation also increased the deposition of the ECM component hyaluronan (HA) in the lung stroma and it was enriched in B16F0 containing metastatic nodules. HA binding through its cognate receptor CD44 correlates with an increase in the metastatic potential of B16 melanoma cells. However, deletion of CD44 using CD44-/- mice or CD44-/- B16F0 cells did not affect inflammation-driven increases in metastasis. Chondroitin sulphate (CS) was found to negatively regulate HA binding in B16 cells, and CS-null CD44 constitutively bound high levels of HA unlike parental B16F0 cells. Thus, high HA binding may be required for effects on metastasis, or HA may be priming the inflammatory premetastatic niche in a CD44 independent manner. Taken together these findings illustrate the importance of the microenvironment in distant site metastasis and they highlight inflammation as an important modifier of this microenvironment.
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