Transformed fibroblasts coinoculated with epithelial cells accelerated the growth and shortened the latency period of human epithelial tumors in athymic mice. Addition of NbF-1 fibroblasts caused epithelial tumors to grow from five marginally tumorigenic or "nontumorigenic" (nontumorforming) human tumor cell lines or strains: PC-i (prostate), WH (bladder), , and cells derived from the ascites fluids of patients with metastatic renal pelvic or prostate cancers. Evidence for the human and epithelial nature of these experimental tumors was provided by histologic, immunohistochemical, Southern and dot-blot hybridization, and cytogenetic analyses. Transformed fibroblasts induced predominantly carcinosarcomas, whereas nontumorigenic fibroblasts (NIH 3T3) and lethally irradiated transformed fibroblasts induced exclusively carcinomas. The fibroblast-epithelial interaction appears to occur bidirectionally and does not result from cell fusion. Because coculture experiments in vitro did not demonstrate an increased cell proliferation, it appears that undefined host factors can influence tumor growth. This tumor model may be useful in drug-screening programs and in mechanistic studies of factors regulating human tumor growth and progression.Interactions between epithelium and mesenchyme mediate crucial aspects of normal development and are also believed to be important in neoplasia (1)(2)(3)(4). By employing tissuerecombination techniques, it has been demonstrated that the growth and differentiation of normal epithelium is regulated either inductively or permissively by neighboring mesenchymal components (5, 6). Studies of stromal-epithelial interaction in the prostate gland revealed that mesenchyme isolated from the fetal urogenital sinus (7, 8) but not from the prostate of newborns (9) or adults (10) can stimulate proliferation of well-differentiated adult epithelium. Mesenchymal mediation of sex steroid action on glandular epithelium has also been demonstrated. The growth of the prostate (7, 8), the regression of the mammary gland by androgen stimulation (11,12), and the growth (13) and the expression of progesterone receptors (14) by the mammary epithelium in response to estrogen have been shown to be mediated by the indirect action of sex steroids on the fibromuscular stroma.Stromal influences on epithelial neoplasia have also been documented in the salivary gland (15), the mammary gland (16), the urinary bladder (17), and the skin (18 Tumorigenicity Determinations. The athymic nude BALB/c mouse strain (20-25 g, Charles River Breeding Laboratories) was used in all experiments. Tumor volumes were calculated by the formula weight x length x height x 0.5236 (24). With the exception of the PC-3 cell line (25), our definition of "tumorigenicity" conformed to the published data. Dot Blot and Southern Hybridization. DNA was prepared from tissues and tumors according to the method described by Davis et al. (26), with slight modification to include treatment steps with proteinase K (0.2 mg/ml, Sigma) and RNase A (20 ,g/...

Responses to the genotoxic effect of bleomycin in lymphocytes of blood cultures, expressed as the average number of chromatid breaks per cell (b/c), varied from less than 0.20 to more than 2.00 in 335 normal individuals. More than 11% of the subjects tested showed a b/c rate above 1.00 and more than 22% showed a b/c rate above 0.80. These individuals are considered sensitive to this radiomimetic drug. The distributional profile of bleomycin responses of the control individuals appears to be representative of the normal human population. In patients with cancers of the colon (83), upper aerodigestive tract (head/neck) (77), and lung (71), the frequencies of subjects in the hypersensitive class were found to be between 40 and 50%, and the response profiles were distinctly different from those of the control population. On the other hand, in a group of elderly cigarette smokers, who exhibited no symptoms of lung cancer, the bleomycin sensitivity profile was significantly skewed toward the more resistant stratum, with only one hypersensitive case among 56 individuals tested (1.78%). The sensitivity profile of patients with breast cancer (82) was similar to that of the control population. Our data suggest that: (1) mutagen sensitivity may play an important role in carcinogenesis of organs and tissues that have direct contact with the external environment (respiratory, digestive, and integumentary systems); (2) it appears to have no significant influence on carcinogenesis of tissues that are not directly exposed to the environment (e.g., breast, brain); and (3) it also has little impact on carcinogenesis in individuals with a hereditary predisposition to cancer (e.g., retinoblastoma, Gardner's syndrome). Development of more effective and precise test systems for carcinogen sensitivity is highly desirable for identification of persons at risk.

More accurate risk estimation can define susceptible subgroups who might be targeted for intensive behavioral interventions, surveillance through screening, and enrollment in chemoprevention programs.

Translocations involving entire chromosomes or whole chromosome arms may not necessarily require deletion of a centromere. Conceivably, in the process of centromeric or telomeric fusion or of fusion of a centromere with a telomere, centromeric inactivation may occur, thus preserving both centromeres—one functional, the other latent—in the resultant translocation chromosome. If such latent centromeres exist and, in addition, are capable of being reactivated, it would explain how additional functional centromeres are acquired in the reverse process of chromosomal fission or fragmentation. A system of nomenclature is proposed for identifying the origin and nature of these chromosomal rearrangements.

The development of head and neck cancer may depend not only on exposure to environmental carcinogens but also on a genetically based susceptibility to carcinogen-induced damage. This thesis presents a case-control study that demonstrates the significance of mutagen sensitivity, a measure of an individual's intrinsic DNA repair capacity against free radical damage, as a risk factor for the disease. As part of the case-control analysis, 167 previously untreated patients and 177 age- and sex-matched healthy controls were assessed for various lifestyle factors including tobacco and alcohol habits, occupational exposures, and diet. Mutagen sensitivity expressed by each individual was determined by quantifying bleomycin-induced chromosomal breaks within peripheral blood lymphocytes in vitro. Consistent with our initial observations and those of others, mutagen hypersensitivity was strongly associated with increased risk of head and neck cancer (odds ratio, 4.95; 95% confidence interval, 2.67 to 9.17) after adjusting for age, sex, and race. Low intake of vitamins C and E was also associated with an increased risk of disease and was interactive with mutagen sensitivity in risk estimates. Individuals with both a low intake of various antioxidants and increased chromosomal sensitivity to oxidant-induced DNA damage were at greatest risk. This study supports the concept that the risk of head and neck cancer is determined by a balance of factors that either enhance or protect against free radical oxygen damage, including innate capacities for DNA repair.