Retinoid and carotenoid angiogenesis: a possible explanation for enhanced oral carcinogenesis.
The carotenoids beta-carotene and canthaxanthin and the retinoid 13-cis-retinoic acid (13-RA) have inhibited oral carcinogenesis in the hamster cheek pouch (16 wks, 3 times/wk at 1.4 mg/kg) induced by an 0.5% solution of 7, 12-dimethylbenz[a]anthracene (DMBA). However, 13-RA at a higher dose (> 2.0 mg/kg per treatment) increased squamous cell carcinoma growth (Eur J Cancer Clin Oncol 24, 839-850, 1988). 13-RA, beta-carotene, and canthaxanthin administered to 60 hamsters (16 wks, 3 times/wk, 10 mg/kg) altered neovascularization characterized by immunohistochemistry for transforming growth factor-alpha (TGF-alpha) and factor VIII. 13-RA + DMBA resulted in more smaller-sized tumors, with a reduced volume and tumor burden (tumor controls, 185.9; 13-RA + DMBA, 151.0). The carotenoids reduced the number and the sizes of the carcinomas formed (beta-carotene, 60 tumors, 142.3 x 10(3) mm3; canthaxanthin, 30 tumors, 116.1 x 10(3) mm3). Factor VIII and TGF-alpha were expressed in high intensity at cancer sites of the 13-RA + DMBA and DMBA groups with > 50 and > 10 cells, respectively, per x 400 field. In contrast, beta-carotene- and canthaxanthin + DMBA-treated pouches showed > 20 and 5 cells, respectively, per x 400 field for factor VIII and TGF-alpha. These results suggest that 13-RA treatment may increase vascular growth, but the carotenoids also produced enhanced levels of endothelial cell growth and TGF-alpha compared with the untreated mucosa. The carotenoids may enhance tumor growth under the appropriate carcinogenic environment.
Schwartz
J L
JL
Department of Oral and Maxillofacial Surgery, Howard University School of Dentistry, Washington, DC 20059, USA. lazar@crols.com
Shklar
G
G
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016644:Canthaxanthin / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000139:chemically induced; D002610:Cheek; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000032:analysis; D007124:Immunoenzyme Techniques; D015474:Isotretinoin / Q000008:administration & dosage*; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000737:chemistry; D009062:Mouth Neoplasms / Q000098:blood supply* / Q000139:chemically induced*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D016211:Transforming Growth Factor alpha / Q000032:analysis; D019207:beta Carotene / Q000008:administration & dosage*
D016211:Transforming Growth Factor alpha; D019207:beta Carotene; D016644:Canthaxanthin; D015127:9,10-Dimethyl-1,2-benzanthracene; D005169:Factor VIII; D015474:Isotretinoin