Affiliation of authors: Laboratory of Human Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Bethesda, MD.
Correspondence to: Curtis C. Harris,
M.D., National Institutes of Health, Bldg. 37, Rm. 2C01, Bethesda, MD 20892-4255 (e-mail: Curtis_Harris{at}nih.gov).
Current address: S. Ambs, ARIAD Pharmaceuticals Inc., 26 Landsdowne St.,
Cambridge, MA 02139.
Cellular expression of inducible nitric oxide synthase, also called NOS2, has recently been shown in various types of human cancer (1-4). NOS2 was mainly found in tumor-infiltrating monocytes and endothelial cells of breast, gastric, and colon tumors (1,2) but was most commonly detected in the epithelium of esophageal (3) and head and neck (4) carcinomas. Thus, tumor-associated nitric oxide production may contribute to the pathogenesis of human cancers by various mechanisms. We recently reported that expression of NOS2 might cause specific p53 mutations in human colon tumors, i.e., C to T transitions at CpG sites, and a decreased frequency of other mutations (1). In this issue, Gallo and co-workers report a statistically significant correlation between the expression of NOS2 and the presence of mutated p53 in tumor cells of head and neck cancer when compared with tumors with wild-type p53. Moreover, the combination of both NOS2 and mutated p53 correlated stronger with an increased vessel density of the tumor than the combination of NOS2 and wild-type p53. Similar findings were made in a xenograft model by the use of human cancer cells that had either wild-type or mutant p53 and expressed constitutively a NOS2 transgene (5). The authors also confirmed previous data (4) that revealed a strong positive correlation between the expression of nitric oxide synthase and tumor angiogenesis and tumor progression. A cellular colocalization of NOS2 and mutated p53 was not observed in colon tumors. NOS2 was found to be highest in adenomas. Because p53 mutations mainly arise at the transition from adenoma to carcinoma in situ, we hypothesized that the strong association of NOS2 with the frequency of G : C to A : T mutations at the CpG dinucleotide sequence in carcinomas is the result of NO-induced mutagenesis. Although the results of Gallo and co-workers are solely based on correlations, the data indicate that mutated p53 may permit cancer cells in head and neck cancer to express higher levels of NOS2 when compared with wild-type p53 cancer cells. While this is the conclusion of Gallo and co-workers, we cannot exclude the hypothesis that p53 mutations coincide with NOS2 because the mutations have been caused by nitric oxide released from NOS2. The determination of NOS2 expression levels at different stages of head and neck cancer should provide more clues about which event is first, a mutated p53 or NOS2, since the frequency of p53 mutations increases with the progression of head and neck cancers (6). If the hypothesis is correct, NOS2 activity should also increase with the progression of head and neck cancer. Nevertheless, the findings of Gallo and co-workers are of interest because they implicate the combination of mutated p53 and NOS2 with tumor progression. In support of the author's hypothesis is a recent investigation that compared NOS2 expression in p53 knockout mice with the expression in the wild-type p53 counterpart (7). Extending our earlier in vitro studies, we found that wild-type p53 transcriptionally represses C. parvum-induced NOS2 expression, thus supporting the existence of a negative feedback loop between NOS2 and wild-type p53. We also detected increased basal levels of NOS2 in the spleen of p53 knockout animals but not in the liver. It remains unclear whether basal NOS2 expression in the spleen of the p53 knockout mice is the result of an endogenous immunologic stimulus. A p53 mutation may not lead to a spontaneous increase of NOS2 but may permit a higher cytokine-induced NOS2 expression. The effect of a p53 mutation on NOS2 expression levels may also be cell type specific. In fact, when we studied basal NOS2 expression in more than 40 human cancer cell lines either with wild-type or mutant p53, NOS2 expression was found in only two cell lines, SW480 and DLD-1, that both have a mutant p53, but most of the cell lines with mutant p53 did not express NOS2. Therefore, the interrelationship between NOS2 and p53 is an active area of investigation in the field of carcinogenesis, which may have implications in cancer prevention and treatment.
REFERENCES
1
Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM,
Harrington AM, et al. Relationship between p53 mutations and inducible nitric oxide synthase
expression in human colorectal cancer. J Natl Cancer Inst 1999;91:86-8.
2 Thomsen LL, Miles DW. Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev 1998;17:107-18.[Medline]
3 Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res 1998;58:2929-34.[Abstract]
4
Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I,
Vergari WA, et al. Role of nitric oxide in angiogenesis and tumor progression in head and neck
cancer. J Natl Cancer Inst 1998;90:587-96.
5 Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, et al. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med 1998;4:1371-6.[Medline]
6 Boyle JO, Hakim J, Koch W, van der Riet P, Hruban RH, Rao RA, et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 1993;53:4477-80.[Abstract]
7
Ambs S, Ogunfusika MO, Merriam WP, Bennett WP, Billiar TR,
Harris CC. Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53
knockout mice. Proc Natl Acad Sci U S A 1998;95:8823-8.
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