tretinoin and Tracheal-Neoplasms

The expression of cornifin, a putative cross-linked envelope precursor, was investigated in several squamous differentiating tissues by in situ hybridization and immunohistochemical analysis. Cornifin mRNA and protein, which are absent in the normal mucociliary tracheal epithelium, are induced in the suprabasal layers of the squamous metaplastic tracheal epithelium of vitamin A-deficient hamsters. Similar to the induction of squamous metaplasia in vivo, culture of rabbit tracheal cells in the absence of retinoids results in squamous differentiation and expression of cornifin. This induction of cornifin expression is suppressed by retinoic acid and several of its analogs. Cornifin mRNA and protein are also detected in the suprabasal layers of the squamous epithelium of rabbit esophagus and tongue. The distribution of cornifin in human epidermis was compared with that of two other crosslinked envelope precursor proteins, involucrin and loricrin. The localization of cornifin and involucrin is very similar. Both are induced in the spinous layer and appear at an earlier stage during epidermal differentiation than loricrin. The expression of cornifin is greatly increased in psoriatic skin. Cornifin mRNA is barely detectable in normal epidermis, whereas it is present at relatively high levels in the suprabasal layers of psoriatic epidermis. Topical treatment with RA results in thickening of the skin and increases the level of cornifin mRNA and protein in the upper spinous layers of mouse skin. Cornifin expression correlates generally with squamous differentiation in a variety of tissues and is abnormally regulated in psoriatic skin and in skin treated topically with retinoic acid.

Topics: Administration, Topical; Animals; Cells, Cultured; Cornified Envelope Proline-Rich Proteins; Cricetinae; Esophagus; Gene Expression; Humans; Male; Membrane Proteins; Mice; Protein Precursors; Psoriasis; Rabbits; RNA, Messenger; Skin; Trachea; Tracheal Neoplasms; Tretinoin; Vitamin A Deficiency

In this paper we examined the effects of transforming growth factor beta (TGF beta) on the proliferation and differentiation of rabbit tracheal epithelial cells in primary culture. Treatment of these cells with TGF beta inhibits cell proliferation in a time- and dose-dependent manner; concentrations as low as 1 pM are able to inhibit cell growth. Concomitantly, TGF beta causes cells to accumulate in the G0/G1 phase of the cell cycle and a sharp reduction in the ability of the cells to form colonies after subculture at clonal density. These results indicate that TGF beta induces terminal cell division in these cells. The inhibition of cell growth is accompanied by changes in cell morphology and a stimulation of the formation of cross-linked envelopes. TGF beta enhances the levels of transglutaminase activity and cholesterol sulfate, two markers of squamous differentiation. Our results indicate that TGF beta induces terminal squamous cell differentiation in rabbit tracheal epithelial cells. Retinoic acid (RA) does not affect the commitment to terminal cell division induced by TGF beta, but inhibits the expression of the squamous phenotype. Growth of normal human bronchial epithelial cells was affected by TGF beta in a way similar to that of rabbit tracheal epithelial cells. Several carcinoma cell lines tested were quite resistant to TGF beta, whereas growth of one carcinoma cell line was stimulated by TGF beta. These results indicate that a modified response to TGF beta could be one mechanism involved in the aberrant growth control of malignant cells.

Topics: Animals; Carcinoma; Cell Differentiation; Cell Division; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Growth Substances; Male; Peptides; Rabbits; Trachea; Tracheal Neoplasms; Transforming Growth Factors; Tretinoin

Male Syrian golden hamsters received 12 weekly intratracheal exposures to 0.5% N-methyl-N-nitrosourea with a special catheter. Following exposures, animals were randomized into 4 groups of 63 hamsters and placed on diets of lab meal or meal with 120 mg 13-cis-retinoid acid (CRA)/kg, 327 mg ethyl retinamide (ER)/kg, or 343 mg N-(2-hydroxyethyl)retinamide (HR)/kg for 6 months at which time all hamsters were killed. The observed incidences of tracheal epithelial neoplasms (No. of animals with tumors/total No. of animals) were 10/63 (lab meal), 22/61 (CRA), 24/63 (ER), and 17/62 (HR). The incidence of carcinomas (No. of animals with tumors/total No. of animals) were 4/63 (lab meal), 12/61 (CRA), 12/63 (ER), and 11/62 (HR). The weight loss and mortality relative to those in the group fed the lab meal were significantly in the group fed HR but not in the other retinoid-treated groups.

Topics: Amyloidosis; Animals; Carcinoma; Cricetinae; Isotretinoin; Male; Mesocricetus; Methylnitrosourea; Neoplasms, Experimental; Precancerous Conditions; Probability; Tracheal Neoplasms; Tretinoin

The effect of 2 retinoids, 13-cis-retinoic acid and 4-methoxy-2,3,6-trimethylphenyl analog of retinoic acid ethyl amide (designated Roll-1430), on tracheal tumor development in hamsters exposed to N-nitroso-N-methylurea was tested. Hamsters were intratracheally exposed either 18, 20, or 23 times to 1% N-nitroso-N-methylurea before the retinoids were administered in the diet. Evidence was presented which indicates that the great majority of the animals are free of invasive neoplasia at the start of retinoid feeding. In none of the 6 retinoid-treated groups could a statistically significant inhibition of tumor development be demonstrated. Hamsters treated with 13-cis-retinoic acid (128 or 172 mg/kg of diet) tended to have an elevated cancer risk; this effect was at a statistically significant level in the group treated with 172 mg/kg of diet. The distribution of histologic tumor types seemed to be shifted in favor of adeno and mixed adeno-epidermoid tumors in the group receiving a low carcinogen dose and Roll-1430. Similar to earlier studies with retinyl acetate tested in hamsters and rats, 13-cis retinoic acid and the retinoic acid ethyl amide analog Roll-1430, failed to inhibit development of respiratory tract neoplasms. We suspect that the reason for this is the absence of significant promoting influences in the current lung cancer models and that retinoids act mostly as anti-promoters.

Topics: Animals; Carcinogens; Cricetinae; Isotretinoin; Male; Mesocricetus; Methylnitrosourea; Survival Rate; Tracheal Neoplasms; Treatment Failure; Tretinoin