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Evidence That Inflammation Encourages Pulmonary Adenocarcinoma Formation in Mice^*

Clinical Implications

^* From the University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Alvin M. Malkinson, PhD, The University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262; e-mail: al.malkinson{at}uchsc.edu

Epidemiologic associations between inflammation and lung cancer include an increased cancer risk in COPD and asthma patients, familial clustering of pulmonary inflammatory diseases and lung cancer, and a decreased cancer incidence among long-term aspirin users. Experimental evidence that inflammation enhances the development of lung tumors in mice includes the following: chromosomal sites that determine susceptibilities to lung injury/inflammation in response to environmental toxins also regulate lung tumor susceptibility; reduced or raised tumorigenesis in mice that are null for, or that overexpress, enzymes that synthesize inflammatory mediators and their receptors; decreased tumor formation following the administration of antiinflammatory drugs such as budesonide and indomethacin; biochemical markers of inflammation such as the elevated expression of enzymes catalyzing eicosanoid biosynthesis and nitric oxide formation within and adjacent to tumor sites; and the incursion of activated inflammatory cells into and peripheral to the tumor mass.

This association between inflammation and neoplasia opens up new avenues for investigating the mechanisms of neoplastic progression, such as the shifting intercellular communication between mutated epithelial cells and inflammatory cells (ie, macrophages, lymphocytes, and mast cells), and determining which inflammatory mediators act at different stages of progression. Practically, this association affords the potential for exploring new biomarkers of early disease (eg, increased serum surfactant protein-D,¹ increased the exhalation of nitric oxide by lung cancer patients²), using anti-inflammatory drugs to prevent the growth of early lesions and even to cause their regression, and to consider including such drugs in combination therapy with cytotoxic agents during more advanced disease stages. Even negative results in the mouse model (eg, our finding that celecoxib not only does not diminish the number of chemically induced tumors but actually enhances their rate of growth³) will be informative in the safe and effective design of prevention trials in high-risk groups and in understanding the interplay of different mediators. The eventual identification of the genes that influence inflammation, and hence tumorigenesis, the delineation of the proinflammatory and antiinflammatory mediators that participate in neoplastic conversion, and the detection of additional inflammatory markers in body fluids that may indicate incipient neoplasia will have practical consequences.

	Footnotes

 
This research was supported by USPHS grants CA33497 and CA96133.

	References

TOP References

 

1. Zhang, R, Pao, W, Umphress, SJ, et al (2003) Serum levels of surfactant protein D are increased in mice with lung tumors. Cancer Res 63,5889-5894[Abstract/Free Full Text]
2. Liu, CY, Wand, CH, Chen, TAC, et al Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer 1998;78,534-541[ISI][Medline]
3. Kisley, L, Barrett, BS, Dwyer-Nield, LD, et al Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice. Carcinogenesis 2002;23,1653-1660[Abstract/Free Full Text]

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