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C M Aldaz

Publications and source records attributed to C M Aldaz.

64 records · Page 4Linked to original sources
PubMed1987

Progressive dysplasia and aneuploidy are hallmarks of mouse skin papillomas: relevance to malignancy.

We report a systematic histopathologic study of papillomas at different times during promotion, correlating the results with those from cytogenetic analysis of the same tumors. Papillomas were induced in SENCAR mice by two-stage carcinogenesis (7,12-dimethylbenz[a]anthracene and phorbol 12-myristate 13-acetate). Individual tumors were randomly sampled at different times during promotion, and histopathologic and cytogenetic studies were carried out on every tumor. Early during promotion (10 weeks), most papillomas were well-differentiated hyperplastic lesions with mild or no cellular atypia. No tumors showed severe dysplastic changes. By 20 weeks of promotion, a dramatic drop had occurred in the number of lesions with no dysplasia. Most of the tumors presented moderate dysplasia, and some already showed severe dysplastic changes. At later stages (30-40 weeks), most of the papillomas were classified as moderately or severely dysplastic papillomas, and several were considered to be intrapapillomatous carcinomas. This histopathologic evaluation was supported by nuclear measurements performed on papillomas at different time points. Chromosomal abnormalities followed a similar trend. Papillomas seem to start as diploid lesions, but between 10 and 20 weeks of promotion, hyperdiploid cells can be observed in almost every tumor. In some cases the stem line was taken over by aneuploid clones. At 40 weeks of promotion, all papillomas were aneuploid, most of them with hyperdiploid stem lines. A positive correlation was found between the histological and cytogenetic studies, with the most aggressive and atypical tumors being the more aneuploid. These results support the idea that most, if not all, papillomas are truly premalignant lesions in different stages of the potential progression toward malignancy. Chromosomal abnormalities might play an important role in the sequence of events leading to malignancy.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

A direct cytogenetic technique for mouse skin carcinomas and papillomas.

A method was developed for obtaining direct chromosome preparations from SENCAR mouse skin tumors induced by chemical carcinogenesis protocols. Papillomas and squamous cell carcinomas were mechanically dispersed immediately after resection and were placed in a modified Hanks' solution with collagenase, trypsin, hyaluronidase, bovine albumin, and Colcemid. Total exposure to Colcemid did not exceed 1 hr. Metaphases were obtained in 100% of the analyzed specimens, allowing chromosome counting screening for double minutes and, in 50% of the cases, useful G-banded slides. The technique described has produced, for this type of tumor, a higher number of successful G-banded preparations than other previously reported methods for solid tumors. This procedure may be applicable for the study of human solid tumors that are histologically similar to our murine model, such as squamous cell carcinoma of cervix or lung.

Animals↗
PubMed1986

Aneuploidy, an early event in mouse skin tumor development.

It has been suggested that chromosomal alterations can play a role in mouse skin carcinogenesis. These changes have been proposed as a possible mechanism of action of tumor promoters and they have also been related to the conversion of benign papillomas to carcinomas. However, direct evidence showing the chromosomal constitution of these tumors has not been previously described. Here we show the presence of aneuploid cells in very early papillomas and the eventual displacement of the diploid stem line by aneuploid clones at later stages. Squamous cell carcinomas (SCC) induced by the same protocol were highly aneuploid. These results suggest that genomic imbalance produced by aneuploidy may be related to the malignant conversion of the benign papillomas.

Aneuploidy↗
PubMed1986

Allogeneic transplantation of normal epidermal cells and squamous cell carcinomas in SENCAR mice.

A method used in our laboratory for the transplantation of single cell suspensions of epidermis and skin carcinomas is described. Silicone chambers were placed into a subcutaneous granulation tissue formed by the implantation of a glass disk. The skin was closed on top of the chamber by using Michael autoclips. Cells were injected 24 to 48 hr later through the skin using a syringe and needle. The neoformation of epithelia with adnexa was observed when newborn epidermal cells were injected. When a fresh cell suspension of squamous cell carcinoma was used, a typical differentiated carcinoma was formed within 2 to 4 weeks. However, after 4 weeks, some of the grafts showed mild signs of rejection. The technique described is a useful system to transplant squamous cell carcinomas and can also be used as a rapid assay for malignancy.

Animals↗
PubMed1986

Effects of chronic topical application of 12-O-tetradecanoylphorbol-13-acetate on the skin and internal organs of SENCAR mice.

Repetitive topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 37 to 52 weeks induced a sustained epidermal hyperplasia, hyperplasia of hair follicles, and increased dermal cellularity in SENCAR mice. In addition, after 52 weeks of protracted promoter treatment most animals developed generalized amyloidosis involving liver and spleen, as well as interstitial nephritis. Severe pyelonephritis and papillary necrosis were also frequently seen. Reactive lymphoid hyperplasia was also a frequent finding. Chronic administration of TPA is not an innocuous treatment affecting only the interfollicular epidermis. The general effect of the promoter on the animals was a marked decrease in their longevity, probably through impairment of the immune system.

Administration, Topical↗
PubMed1986

Critical genetic determinants and molecular events in multistage skin carcinogenesis.

Carcinogenesis can be operationally and mechanistically divided into at least three major stages--initiation, promotion, and progression. Variations among stocks and strains of mice to susceptibility to multistage skin and liver carcinogenesis appear to be more related to alterations in tumor promotion than tumor initiation; however, the critical events have not been determined. In the mouse skin model the first stage is thought to involve the interaction of a tumor initiator with the genetic material of stem cells leading to an alteration in some aspect of growth control, differentiation, or both. The major effect of tumor promoters, regardless of the type, is the specific expansion of the initiated stem cells in the skin. This appears to occur by both direct and indirect mechanisms that involve the loss of glucocorticoid receptors, differentiation alterations, a direct growth stimulation of the initiated cells, or selective cytotoxicity. The progression stage is characterized by a high level of genetic instability that produces a number of chromosomal alterations. These changes may be responsible for the loss of the high-molecular-weight keratin proteins and filaggrin, increase in gamma-glutamyl-transpeptidase activity, and changes in oncogene expression in squamous cell carcinomas. We have found that a high percentage of squamous cell carcinomas have a trisomy in chromosome 2 that carries both src and abl genes and an increased expression of src and abl. We have also found increased Ha-ras on RNA expression in both papillomas and squamous cell carcinomas. We suggest that the genetic instability of the initiated cells is responsible for most observed changes during skin carcinogenesis.

Animals↗
PubMed1986

Cytogenetic evidence for gene amplification in mouse skin carcinogenesis.

Using our recently developed methodology for cytogenetic evaluation of solid tumors, we analyzed the occurrence of double minutes (DM) in chemically induced mouse skin carcinomas and papillomas. These studies revealed that DM were observed in 10% of the squamous cell carcinomas and in none of the papillomas screened. In addition, we analyzed four cell lines derived from mouse skin papillomas and one spontaneously transformed mouse epidermal cell line. The presence of DM was a consistent feature in all the studied cell lines. In the papilloma cell lines, the degree that DM occurred correlated with the cell line's capacity to form malignant tumors in immunosuppressed mice. DM were also observed in direct chromosomal preparations from tumors induced by one of the papilloma cell lines. Homogeneously staining regions were also present in metaphases from the spontaneously transformed cell line. We have shown here, for the first time, DM and homogeneously staining regions in mouse skin tumors and transformed cells derived from mouse skin. Since DM and homogeneously staining regions are the cytogenetic equivalents of gene amplification, which is a mechanism of increased expression of normal or altered gene products, these findings may play a relevant role in mouse epidermal carcinogenesis.

Animals↗
PubMed1985

Cutaneous changes during prolonged application of 12-O-tetradecanoylphorbol-13-acetate on mouse skin and residual effects after cessation of treatment.

The epidermal and dermal effects of protracted 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment (2 micrograms TPA twice weekly) of Sencar mouse skin were studied using cell kinetics and morphometric techniques. In addition, regression of TPA-induced changes was evaluated after cessation of 56 topical applications. During the first week of treatment a reactional hyperplasia, characterized by cell damage, edema, and acute inflammation in both epidermis and dermis, occurred. This picture changed gradually during the following 3 weeks: an epidermal hyperplasia devoid of involutional or inflammatory features was accompanied by a moderate to mild chronic inflammation of the dermis and a hyperplasia of the hair follicles. This remained throughout the experimental period until the topical TPA treatment ceased. Although TPA induced papillomas in only 5% of the animals (maximum = 2 papillomas/animal and no carcinomas), all sustained marked epidermal hyperplasia of approximately 4 to 5 times the normal thickness, and increased the number and volume of hair follicles. The [3H]thymidine pulse-labeling index of the basal layer was approximately 32% (normal congruent to 6%). The level of dark keratinocytes remained constant; i.e., 8% of the basal cells were identified as dark cells during the entire experiment. At the subepidermal level the dermal thickness and total cellularity increased, although the proportion of the different cell types changed during the treatment. The mast cell population increased remarkably. After TPA treatment ceased, most of these parameters regressed abruptly during the first 2 weeks. Two to 4 months later, the epidermis was slightly thinner, and the labeling index was 50% lower than normal (2.8%). This study shows that prolonged repetitive TPA applications induced a steady-state hyperplasia without tachyphylaxis, and that this alteration regressed rapidly after treatment ceased. In addition, labeling-index values lower than normal were reached soon after normalization, suggesting that a possible selection of keratinocytes, dependent on TPA for proliferation, took place during the chronic administration of topical TPA. The number of hair follicle, capillary vessels, mast cells, and the dermal thickness never reached normal values after treatment. These important changes in the dermis and hair follicles indicate that the target cells for tumor promoters are not confined to the epidermis alone, and that these tissues could participate actively in carcinogenesis directly, either as tumor-originating tissues (hair follicles), or as inducers or helpers of neoplastic growth (connective tissue cells).

Animals↗