Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver
0301 basic medicine
Nitric Oxide Synthase Type III
Antigens, Polyomavirus Transforming
Liver Neoplasms
Down-Regulation
Mice, SCID
Anoikis
Nitric Oxide
Models, Biological
Cathepsin B
Rats
Animals, Genetically Modified
Pancreatic Neoplasms
Mice
03 medical and health sciences
Transduction, Genetic
Cell Line, Tumor
Animals
Humans
Female
Neoplasm Metastasis
Stromal Cells
DOI:
10.2353/ajpath.2008.080158
Publication Date:
2008-09-24T06:27:46Z
AUTHORS (10)
ABSTRACT
Tumor progression is regulated through paracrine interactions between tumor cells and stromal cells in the microenvironment, including endothelial cells and myofibroblasts. Nitric oxide (NO) is a key molecule in the regulation of tumor-microenvironment interactions, although its precise role is incompletely defined. By using complementary in vitro and in vivo approaches, we studied the effect of endothelial NO synthase (eNOS)-derived NO on liver tumor growth and metastasis in relation to adjacent stromal myofibroblasts and matrix because liver tumors maintain a rich, vascular stromal network enriched with phenotypically heterogeneous myofibroblasts. Mice with an eNOS deficiency developed liver tumors more frequently in response to carcinogens compared with control animals. In a surgical model of pancreatic cancer liver metastasis, eNOS overexpression in the tumor microenvironment attenuated both the number and size of tumor implants. NO promoted anoikis of tumor cells in vitro and limited their invasive capacity. Because tumor cell anoikis and invasion are both regulated by myofibroblast-derived matrix, we explored the effect of NO on tumor cell protease expression. Both microarray and Western blot analysis revealed eNOS-dependent down-regulation of the matrix protease cathepsin B within tumor cells, and silencing of cathepsin B attenuated tumor cell invasive capacity in a similar manner to that observed with eNOS overexpression. Thus, a NO gradient within the tumor microenvironment influences tumor progression through orchestrated molecular interactions between tumor cells and stroma.
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