The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth.

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The effect of lauric acid (LA), which is reported to induce cyclooxygenase (COX)-2 expression in macrophage cells (RAW 264.7) on the development of aberrant crypt foci (ACF), putative precursor lesions of colonic adenocarcinoma, was investigated in an inflammation-related mouse colon carcinogenesis model treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). To induce ACF, male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight) and then followed by 1% DSS in drinking water for one week, starting one week after dosing of AOM (AOM/DSS group). The AOM/DSS/LA group was fed with a diet containing 1% LA for 7 weeks, starting one week after the cessation of DSS administration. Other groups included the AOM/LA group given AOM and 1% LA diet for 9 weeks, the DSS/LA group given DSS and the diet with 1% LA, the AOM group that received AOM alone, the DSS group given DSS alone in drinking water, the LA group fed with 1% LA-containing diet alone, and the untreated group. At week 10 (end of the study), the frequency of ACF did not significantly differ between the AOM/DSS group (7.4 ± 3.0) and the AOM/DSS/LA group (8.4 ± 5.0). The value was extremely low in the AOM/LA group (1.0 ± 1.0) and in the AOM alone group (2.4 ± 2.7). No ACF developed in other groups. Our findings suggest that dietary LA did not influence the occurrence of ACF in the AOM/DSS-induced mouse colon tumorigenesis, indicating a lack of LA enhancing effects on the early phase of inflammation-related mouse colon carcinogenesis.

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This report describes spontaneous occurrence of erythroid leukemia in a 6 week-old male Crlj:B6C3F₁ mouse. Macroscopically, severe hepatosplenomegaly was noted, but no abnormalities were observed in other tissues including the thymus and lymph nodes. Hematological examinations of blood and bone marrow smear preparations revealed marked proliferation of erythroid cells at various stages of maturation, but neither obvious atypia nor neoplastic proliferation of granulocytic cells was observed. Microscopically, there was marked infiltration of neoplastic erythroid cells into the hepatic sinusoids, splenic red pulp, and bone marrow, but there was no infiltration into the thymus or lymph nodes. Corresponding to the hematological findings, no distinct proliferation of granulocytic cells was detected microscopically. Immunohistochemical examination revealed that these cells were positive for hemoglobin. The present case of mouse erythroid leukemia closely resembles "pure erythroid leukemia" in humans.

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A grayish white nodule, 1.0 × 1.0 × 2.0 cm in size, was grossly observed in the liver of a 110-week-old male CD-1 mouse. Microscopically, the lesion was characterized by two types of proliferation area, one of which was composed of a lipomatous proliferation with small spindle cells and severe extramedullary hematopoiesis (EMH). The other area was composed of large spindle cells closely proliferating along the hepatic cords. The proliferative lesion was partly positive for vimentin and had increased amounts of laminin, which is an extracellular matrix protein synthesized by Ito cells. Ultrastructurally, the lipomatous area contained cells with individual lipid droplets in the cytoplasm. The characteristic findings of this nodule were similar to those of Ito cell tumors in mice reported previously, except for the severe EMH in our case.

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We report a case of bilateral ovotestes in a female beagle dog. This dog was used in a 4-week repeated-dose toxicity study and sacrificed by exsanguination at 6 months of age. Clinical observation, hematological examination, blood chemistry analysis, urinalysis and autopsy did not reveal any abnormal or drug-induced effects. Microscopically, seminiferous-like tissue was observed in the medulla of the bilateral ovaries. The morphological and immunohistochemical characteristics of Sertoli-like cells lining the seminiferous-like tubules corresponded to those of Sertoli cells in the testis. Myoid-like cells exhibiting positive reactions for alpha smooth muscle actin surrounded the seminiferous-like tubules. Therefore, the dog was regarded as a case of true hermaphroditism with bilateral ovotestes. PCR using DNA extracted from paraffin-embedded sections of the testicular parts of the ovotestis, uteri and spleen showed that the organogenesis of ovotestes in this case was not associated with the sex-determining region Y gene.

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