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, Gregory James Gores, Vijay Shah

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1002-1012
Number of pages11
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
StatePublished - Oct 2008

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Tumor Microenvironment
Stromal Cells
Nitric Oxide
Liver
Neoplasms
Myofibroblasts
Nitric Oxide Synthase
Anoikis
Cathepsin B
Peptide Hydrolases
Neoplasm Metastasis
Anatomic Models
Cellular Microenvironment
Nitric Oxide Synthase Type III
Liver Neoplasms
Pancreatic Neoplasms
Carcinogens
Blood Vessels
Down-Regulation
Endothelial Cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. / Decker, Ningling Kang; Abdelmoneim, Soha S.; Yaqoob, Usman; Hendrickson, Helen; Hormes, Joe; Bentley, Mike; Pitot, Henry; Urrutia, Raul; Gores, Gregory James; Shah, Vijay.

In: American Journal of Pathology, Vol. 173, No. 4, 10.2008, p. 1002-1012.

Research output: Contribution to journalArticle

Decker, NK, Abdelmoneim, SS, Yaqoob, U, Hendrickson, H, Hormes, J, Bentley, M, Pitot, H, Urrutia, R, Gores, GJ & Shah, V 2008, 'Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver', American Journal of Pathology, vol. 173, no. 4, pp. 1002-1012. https://doi.org/10.2353/ajpath.2008.080158
Decker, Ningling Kang ; Abdelmoneim, Soha S. ; Yaqoob, Usman ; Hendrickson, Helen ; Hormes, Joe ; Bentley, Mike ; Pitot, Henry ; Urrutia, Raul ; Gores, Gregory James ; Shah, Vijay. / Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. In: American Journal of Pathology. 2008 ; Vol. 173, No. 4. pp. 1002-1012.
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