Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver

Ningling Kang Decker, Soha S. Abdelmoneim, Usman Yaqoob, Helen Hendrickson, Joe Hormes, Mike Bentley, Henry Pitot, Raul Urrutia, Greg J. Gores, Vijay H. Shah

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1002-1012
Number of pages11
JournalAmerican Journal of Pathology
Issue number4
StatePublished - Oct 2008
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the National Institutes of Health (grants R01 DK059615 to V.H.S., R01 HL86990 to V.H.S., and K01 CA118722-01A1 to N.K.D. ), the Mayo Clinic (pancreatic cancer SPORE seed grant to V.H.S.), and the American Liver Foundation/American Association for the Study of Liver Diseases (2006 Sheila Sherlock grant to N.K.D.).


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