Affiliations of authors: O. Gallo (Institute of Otolaryngology, Head, and Neck Surgery), I. Sardi (Department of Clinical Physiopathology, Medical Genetics Unit), M. Masini (Department of Preclinical and Clinical Pharmacology), A. Franchi (Institute of Anatomic Pathology) University of Florence, Italy.
Correspondence to: O. Gallo, M.D., Istituto di Clinica Otorinolaringiatrica, University of Florence, Policlinico di Careggi, V. le G. B. Morgagni, 85, 50134 Firenze, Italy.
We read with great interest the work by Ambs and co-workers (1) suggesting a clear relationship between p53 (also known as TP53) gene mutations and inducible nitric oxide synthase (NOS2) activity in human colorectal cancer published in the Journal. In this study, the authors postulated that most of the nitric oxide (NO) released in colon neoplastic tissues is produced from tumor-infiltrating mononuclear cells and is produced less frequently from endothelial and tumor cells. Because of the reported mutational effect of high NO levels in p53 complementary DNA, resulting mainly in G : C to A : T transitions at CpG dinucleotides (2), they argue that tumor-associated NO production may modify DNA directly, inducing p53 mutations in exposed cells and providing a strong selection pressure in mutated cells during colon carcinogenesis. Recently, the same group also reported that in athymic nude mice, colon cancer cells overexpressing NOS2 with mutated p53 had accelerated tumor growth associated with increased vascular endothelial growth factor expression (VEGF) and neovascularization (3), extending our previous observations among NOS2 activity and tumor angiogenesis in human epidermoid cancer in vivo(4). According to these findings, p53-mutated tumors due to p53-mediated increased expression of NOS2 activity (5) may release high NO levels which, in turn, have a central role in controlling VEGF-mediated angiogenesis. However, in the same study, the authors postulated that p53 mutations are the chief cause of high NO release by tumor cells because of the lack of p53 wild-type transrepression of NOS2 (5).
We have recently analyzed NOS2 activity in head and neck cancers (HNC), which are
characterized by a high incidence of p53 mutations, mainly of G : C to A : T transitions at CpG
dinucleotides (6). At variance with the colon cancer model, we found that
cancer cells in the head and neck area were strongly immunoreactive with anti-NOS2 antibodies in
comparison with endothelial and tumor-infiltrating inflammatory cells. In agreement with the
analysis done by Ambs and co-workers (1), preliminary results on 27
HNC tissue samples confirm a clear correlation between p53 mutations and NOS2 activity. We
found that p53-mutated HNC (14 case patients) detected by single-stand conformation
polymorphism (SSCP) showed higher levels of NOS2 messenger RNA (Fig. 1) and activity (median, 5.67; range, 2.03-8.76 pmol/min/mg protein) as well as cyclic
guanosine monophosphate (cGMP) (the mediator of the response of cells to NO) levels (median,
5.67; range, 3.23-8.67 fmol/mg protein) in comparison with p53 wild-type tumors (NOS2
activity: median, 2.89; range, 1.94-6.71 pmol/min/mg protein; cGMP activity: median, 2.33,
range, 1.85-5.66 fmol/mg protein) (Wilcoxon test; P<.001); normal control mucosa
showed a median baseline NOS2 activity of 0.95 (range, 0.59-2.93 pmol/min/mg protein) and a
median cGMP level of 2.97 (range, 1.87-4.96 fmol/mg protein). Moreover, we confirm a clear
correlation between NOS2 activity, cGMP levels, and tumor angiogenesis (assessed by
microvessel counts) in both p53-mutated and p53 wild-type HNC (Wilcoxon test; P
= .01 and P = .04 for correlation between NOS2 activity and micovessel
density in p53-mutated and p53 wild-type HNC, respectively; P = .001 and P = .03, for correlation between cGMP and microvessel counts in p53-mutated and
p53 wild-type HNC, respectively). Furthermore, preliminary results in 15 preinvasive head and
neck lesions that progressed to invasive carcinoma indicate an analogous trend among p53 gene
mutation and NOS2 overexpression (four of six lesions with p53 mutations showed NOS2
overexpression in comparison with three of nine p53 wild-type lesion), suggesting that NOS2 as
well as p53 mutation are both an early event in the multistep process of head and neck
carcinogenesis.
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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 Murata J, Tada M, Iggo RD, Sawamura Y, Shinohe Y, Abe H. Nitric oxide as a carcinogen: analysis by yeast functional assay of inactivating p53 mutations induced by nitric oxide. Mutat Res 1997;379:211-8.[Medline]
3 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]
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, Ogunfusika MO, Merriam WG, 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.
6
Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH,
Eby YJ, et al. Association between cigarette smoking and mutation of the p53 gene in
squamous-cell carcinoma of the head and neck. N Engl J Med 1995;332:712-7.
7 Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, et al. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer 1998;78:233-9.[Medline]
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