Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis

Summary One way to explain the development of head and neck cancer is through the theories of field cancerization, i.e., the exposure of an entire field of tissue to repeated carcinogenic insult, and multistep process, i.e., development of multiple cancers in a predisposed field through a series of recognizable states. Recent molecular genetic studies of histologically normal and prealignant epithelia of high-risk subjects and studies of malignant tumors in aerodigestive tract epithelia have identified a continuum of accumulated specific genetic alterations that possibly occur during the clonal evolution of tumors, namely, during the multistep process. Second primary or multiple primary tumors arise in the same fields as independent clones, with similar but unique molecular genetic and/or cellular alterations. Consequently, the assessment of these genetic and phenotypic alterations has been integrated into clinical chemoprevention trials in an effort to identify biomarkers that are also risk predictors and intermediate end points. This review covers candidate biomarkers of the processes of field cancerization and multistep tumor development in aerodigestive tract epithelia, including general and specific genetic markers, proliferation markers, and squamous differentiation markers.     

Genetic factors controlling inheritance of susceptibility to 1,2-dimethylhydrazine

Summary Reciprocal crosses were made between AKR/J, a 1,2-dimethylhydrazine (DMH)-resistant mouse strain, and SWR/J, a sensitive strain. The F1 hybrids were tested with DMH and methylazoxymethanol (MAM), two colon carcinogens. Either DMH (20 mg/kg body weight) or MAM (35 mg/kg body weight), a metabolic derivative of DMH, was injected weekly for 10 weeks. In each group of 35 mice, 10 were injected with tritiated thymidine (25 Ci) 1 week after the sixth injection of DMH and MAM for the evaluation of proliferative characteristics and the number of foci of dysplasia occuring in 325 m of distal colonic mucosa. At 27 weeks after the first injection of the carcinogen, the colons of remaining mice were opened longitudinally and the number of tumors enumerated. Compared with DMH-treated mice, the number of foci of dysplasia per mouse, the percentage of tumor-bearing mice, the number of tumors per animal, and the number of tumors per tumor-bearing animal induced by MAM were severalfold higher. This would suggest the presence of a gene(s) repressing metabolism of DMH to MAM. Moreover, differences in response to the carcinogens were observed between the sexes. In contrast to males, females treated with both DMH and MAM had significantly greater numbers of tumors per animal, tumors per tumor-bearing mice, and a greater proliferative response with extension of S-phase cells to the upper third and luminal surface of crypts. Among males, those with the X^AKR/Y^SWR heritage appeared more resistant than X^SWR/Y^AKR males, particularly in their response to MAM. A twofold difference in the number of foci of dysplasia per mouse, tumors per animal, and the number of tumors per tumor-bearing animals was seen. Analyses of the response to DMH and MAM by F1 reciprocal hybrids of the AKR and SWR strains have shown a complex inheritance pattern governing susceptibility to DMH. Resistance to the carcinogen is provided by at least two specific repressor genes, one governing metabolism of carcinogen from DMH to MAM, and the other controlled by gender. Genetic factors contributed by the AKR female appear to convey additional resistance to male progeny, suggesting more than one gender-related gene.Supported in part by CA 08748 from the National Cancer Institute and by CA 26674 from the National Cancer Institute through the National Large Bowel Cancer Project     

Mouse mammary tumor virus and mammary tumorigenesis in wild mice

The current knowledge of the distribution of the mouse mammary tumor virus (MMTV) proviral genomes and the mechanism of mammary tumorigenesis by MMTV in mice, with the main emphasis on Asian feral mice, is reviewed. The relevant earlier discoveries on the mode of MMTV transmission are summarized to provide an outline of the biology of MMTV. Finally, the viral etiology of human breast cancer will be discussed.     

Prolactin concentration in plasma and susceptibility to mammary tumors in female rats from different strains treated chronically with estradiol-17β

Summary Prolactin is associated with the development of mammary tumors in rats. The aim of the present study was to evaluate whether strain differences in susceptibility to the development of mammary tumors could be explained by genetic differences in the response of the pituitary to chronic stimulation by estrogens. Prolactin levels were measured in plasma from rats of the Sprague-Dawley, Wistar WAG/Rij and Brown Norway BN/BiRij strains before and at different times after subcutaneous implantation of estradiol-17 in cholesterol/paraffin pellets. In all strains plasma prolactin was elevated from the second week after implantation of the pellet, although there were quantitative differences between the responses. At 32 weeks after implantation of the pellets the plasma level of prolactin in Sprague-Dawley rats was 1247 ± 367 ng NIAMDD prolactin RP-1/ml (mean ± S.E.M), whereas Wistar WAG/Rij and Brown Norway BN/BiRij had plasma prolactin levels of 679 ± 211 and 182 ± 19 ng/ml respectively. Between 52 and 104 weeks after implantation these values rose to 4016 ± 1116, 5004 ± 1053 and 808 ± 129 ng/ml respectively. The plasma concentration of prolactin of rats in this age group was strongly associated with the occurrence of pituitary adenomas in all three strains. In untreated rats, the concentration of prolactin in the plasma increased with age to only 200–400 ng/ml at 12–24 months of age but no significant differences were observed between the three rat strains. It is concluded that observed differences in spontaneous and estrogen-mediated mammary tumor development in these rat strains cannot be explained by genetic differences in the plasma concentration of prolactin. The development of malignant mammary tumors after estrogen treatment appears to be associated with the extent of the increase in plasma prolactin induced by the estrogen.     

三种镍化合物诱发转化细胞恶性度的鉴别与分析

目的 :利用已建立的三种镍化合物体外转化细胞进行裸鼠体内成瘤实验研究 ,比较它们恶性度的差异。方法 :三种镍化合物转化细胞接种BALB/C裸鼠 ,进行肿瘤细胞和转化细胞的透射电镜及扫描电镜观察。结果 :硫化镍 ,氯化镍 ,硫酸镍分别诱发的转化细胞都能在BALB/C裸鼠皮下形成肿瘤 ,病理组织学检查确定为纤维肉瘤。经扫描电镜与透射电镜观察瘤细胞形态与转化细胞有一定差别。结论 :本文进一步说明了三种镍化合物所诱发的细胞转化为恶性转化 ,且都具有体内致瘤性。     

Pleural dosimetry and pathobiological responses in rats and hamsters exposed subchronically to MMVF 10a fiberglass.

Interspecies differences in pulmonary and pleural responses to the inhalation of natural mineral and synthetic vitreous fibers have been observed in chronic and subchronic studies. However, the reasons for these differences are not clearly understood. There are also fiber-specific differences in the outcome of chronic inhalation exposure to natural mineral and synthetic vitreous fibers. Whether these differences are dependent upon the ability of these fibers to translocate to the pleural space is unknown. The present study was conducted to compare retained fiber burdens and selected pathological responses in the pleural compartments of rats and hamsters following subchronic inhalation of MMVF 10a fiberglass, a fiber negative for tumorigenesis or fibrosis in chronic studies. Fischer 344 rats and Syrian golden hamsters were exposed for 4 or 12 weeks by nose-only inhalation at nominal aerosol mass concentrations of 45 mg/m3 (610 WHO fibers/cc). Pulmonary fiber burdens and pulmonary inflammatory responses were greater in rats than in hamsters. The total number of fibers in the lung was approximately three orders of magnitude greater than in the pleural compartment. Pleural burdens in the hamster (160 fibers/cm2 surface area) were significantly greater than burdens in similarly exposed rats (60 fibers/cm2 surface area) following 12 weeks of exposure. With time postexposure, pleural burdens decreased in hamsters but were essentially unchanged in rats. Pleural inflammatory responses in both species were minimal. In rats, pleural inflammation was characterized by increased numbers of macrophages and increases in mesothelial cell replication during the period of fiber exposure. In contrast, hamsters had increased numbers of macrophages and lymphocytes, and mesothelial-cell replication indices were elevated on the parietal pleura of the costal wall and diaphragm, with some of these responses persisting through 12 weeks of postexposure recovery. Taken together, the results suggest that differences among rodent species in pleural responses to inhaled fibers are due to a delivered dose of fibers and to the biological responses to the presence of the fibers.     

Small nucleolar RNAs (snoRNAs) as potential non-invasive biomarkers for early cancer detection

Small nucleolar RNAs (snoRNAs) are non-coding RNA (ncRNA) molecules,which are associated with specific proteins to form small nucleolar ribonucleoparticles.However,the function of snoRNAs in cancer still remains elusive.Recently,several independent lines of evidence have indicated that these ncRNAs might have crucial roles in controlling tumorigenesis,and snoRNAs could be potential biomarkers for cancer.