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Alterations of the P53 Tumor Suppressor Gene During Mouse Skin Tumor Progression1

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Alterations of the P53 Tumor Suppressor Gene During Mouse Skin Tumor Progression1 [CANCER RESEARCH 51, 6615-6621, December 15, !9911 Alterations of the p53 Tumor Suppressor Gene during Mouse Skin Tumor Progression1 B. Rugger!, J. Caamano, T. Goodrow, M. DiRado, A. Bianchi, D. Trono, C. J. Conti, and A. J. P. Klein-Szanto2 Department of Pathology, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [B. R., J. C., M. D., A. J. P. K.J; Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486 [T. G.J; and Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Smithville. Texas 78957[A. B., D. T., C. J. C.] ABSTRACT (3-5), and the p53 gene (6, 7). The wild-type p53 gene has been found to act as a bona fide The two-stage murine skin tumorigenesis model is widely used to study the development of squamous cell neoplasias. We have investigated tumor suppressor capable of inhibiting cell transformation in expression of the p53 and retinoblastoma tumor suppressor genes in duced by mutant p53 in collaboration with a variety of activated eight murine skin tumor cell lines of varied histopathology and malignant oncogenes (8,9). Rearrangements or mutations in the wild-type potential, in seven in wvo-derived clones from these cell lines, and in 39 p53 gene have been implicated in the development and progres primary short-term cultures of similarly induced skin tumors at various sion of several human malignancies (10). stages of tumor progression. One squamous cell carcinoma cell line and three more malignant clones derived from it revealed mutations of the Similarly, mutations in both alíelesof the Rb gene resulting p53 protein by immunoprecipitation analyses despite normal-sized p53 in functional inactivation of the Rb protein are not limited to transcripts. Sequence analysis identified the nature of the point mutations retinoblastomas and their associated secondary malignancy, in these lines, a G—»Ctransversionin codon 132. Mouse retinoblastoma osteosarcoma (3). Alterations in Rb have been identified in a transcripts and protein were unaltered in all the cell lines examined. variety of human tumors (11-14) of diverse histopathology, Among short-term cultures of skin tumors, thepSS gene appeared normal suggesting that Kb inactivation may be a common theme in in all papillomas and early well-differentiated carcinomas by Southern and immunoprecipitation analyses. In contrast, four of eight tumors from oncogenesis in neoplasms lacking any etiologic or ontogenic later stages of promotion (50-60 weeks) possessed alterations in p53, relationship to retinoblastoma (14). including loss of the p53 product, and loss of ¡mmunoreactivitywith a The two-stage murine skin carcinogenesis model has been a murine-specific antibody recognizing only wild-type pS3 protein. Loss of valuable system for investigating the molecular and genetic heterozygosity at the p53 locus was similarly observed in several more events involved in tumor initiation, promotion, and progression malignant tumors from later stages of promotion. In contrast retinoblas (15). Its utility as an animal model of carcinogenesis lies in its toma expression was normal regardless of the stage of promotion or histológica! grade of the tumor. Direct sequence analyses of exons 5 use in the study of tumor development and progression in a through 8 of the pS3 gene in eight advanced murine skin tumors revealed mammalian system where the genetic and phenotypic variability a 25% incidence of p53 mutations. These point mutations were located has been reduced by using a single carcinogen ¡na reasonable in codons 245 and 263. Collectively, these data indicate that alterations genetically homogeneous population (15). Moreover, this ani in the p53 gene occur in 25 to 50% of murine skin tumors induced by the mal model for studying the development of squamous cell two-stage tumorigenesis protocol and are later events in murine skin carcinomas of the skin has multiple analogies with epithelial tumor progression. Moreover, these alterations are associated with tu mors possessing a more malignant and/or poorly differentiated neoplasias of the lung, esophagus, head and neck, and urogen phenotype. ital tract (15) and has been widely used to evaluate the carcin- ogenicity and toxicity of environmental agents. A considerable INTRODUCTION body of experimental evidence has demonstrated that over 90% of murine skin tumors, both papillomas and carcinomas, initi Within the past 10 years evidence has accumulated support ated by DMBA and promoted by several types of phorbol esters ing the existence of genes that appear to regulate normal and possess an activated H-ras oncogene with a point-mutated neoplastic cell proliferation. The homozygous loss or ¡nactiva- codon 61 (16-19). In addition to this initial molecular event, tion of these tumor suppressor genes by point mutations, dele aneuploidy and progressive dysplasia are hallmarks of mouse tions, or rearrangements plays a role in tumor development (1, 2). The precise physiological function(s) of these gene products skin papillomas (20, 21). These findings have led to the sugges is not known; potential roles in modulating chromosome sta tion that skin papillomas bear a high degree of genetic instabil bility, gene transcription, cellular proliferation, differentiation, ity, which may increase the probability of a second relevant and cellular senescence have been suggested (1,2). To date, the genetic event, i.e., a mutation or chromosomal loss or re two tumor suppressor genes most extensively characterized and arrangement, which may play a critical role in tumor progres studied have been the retinoblastoma susceptibility gene, Rb3 sion (20, 21). Despite extensive analyses of tumor suppressor genes in Received 6/18/91; accepted 10/28/91. The costs of publication of this article were defrayed in part by the payment various human and animal tumors, alterations or loss of known of page charges. This article musi therefore be hereby marked advertisement in tumor suppressor genes have not been examined in the two- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by NIH Grants CA53713, CA44980, CA06927, stage murine skin carcinogenesis model. It has been hypothe CA53I23, and RR05895, and an appropriation from the Commonwealth of sized that the loss or inactivation of tumor suppressor genes Pennsylvania. 1To whom requests for reprints should be addressed, at Department of may constitute a critical step in murine skin tumor progression, Pathology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia. PA since the karyotypic changes observed during the later stages 19111. 3The abbreviations used are: Rb. retinoblastoma; STC. short-term culture; of carcinogenesis may involve the loss or inactivation of such DMBA. 7,12-dimethy!benz(a)anthracene; PMA. phorbol-12-myristate 13-ace- sequences (see Ref. 22). We sought to investigate these possi tale; MEM, minimal essential medium; cDNA, complementary DNA; PCR, polymerase chain reaction; SCC, squamous cell carcinomas; Aprt, adenine bilities for the p53 and Rb tumor suppressor genes in the murine phosphoribosyltransferase. skin tumorigenesis model. 6615 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1991 American Association for Cancer Research. ALTERATIONS OF THE pS3 TUMOR SUPPRESSOR GENE Table 1 Tumorigenicity and métastasesdatafrom parental murine skin tumor MATERIALS AND METHODS lines and in vivo-derived clones Cell Lines Lung métastases" The murine skin tumor cell lines used in these studies are listed in incidence*9/105/57/79/95/815/152/23/34/44/45/50/161/136/190/50/5Histopathology Table 1. All were maintained in low-calcium (0.05 HIM) minimum CelllineCH72CH72T1CCH72T3CH72T4JWF2JWFT1BB1BB1T1BB1T2BB2BB2T1FBIVT17DTpappll7MT1/2C-50TumorgradeseenSCC colonization0/60/55/73/51/51/83/41/52/22/22/40/180/16 essential medium (Whittaker, Walkersville, MD) supplemented with III-IVsec 1% fetal calf serum and a variety of growth factors as described (23). ivSCC IVsec Induction of Skin Tumors iSCC IVSCC Tumors were induced in SENCAR mice initiated with 10 nmol of IVsec DMBA and subjected to twice-weekly promotion with 2 ¿igPMA as ivsec ivsec detailed previously (20, 21) for varying periods extending up to 60 ivsec weeks. i'Papilloma-SCCIPapilloma-SCCIPapilloma^KeratinocytelineSpontaneous6/102/56/75/92/81/152/21/33/44/4NA*0/130/8Lungivsec Preparation of STCs of Skin Tumors Tumor sections were characterized histopathologically as described (21) following hematoxylin-eosin staining. The majority of tumor tissue was utilized for the preparation of short-term cultures by a modified " Metastasis-bearing animals/total number of animals. cytogenetic technique (24) involving enzymatic dispersion with trypsin, * Tumor-bearing animals/total number of animals. collagenase type II, and hyaluronidase under aseptic conditions as 1T, cloned cell line derived from the in vivo passaging of the parental cell line previously detailed (25). Cells were plated in low-calcium MEM at 5 x in nude mice. These lines are phenotypically distinct, although they possess a 105-2 x IO6 viable cells/25-cm2 dish at 31°C.After 24 h, cells were common parental origin. gently washed in calcium-free Hank's balanced salt solution with gen- •¿*NA,not available. ' Line derived from a Stage I SCC. tamycin (100 ¿ig/ml)(25) and utilized 24 h later for experimental ^ Line derived from a papilloma. analyses. Tumorigenicity and Spontaneous and Experimental Métastases at 37°C(31°Cfor primary STCs) in a humidified COi atmosphere. Nude mice of BALB/c background (8-14 weeks old) were whole- Cultures were labeled with 300 to 600 >iC\of [35S]-L-methionine (Amer- body irradiated (400 rads). Tumor cell lines were resuspended in low- sham) for 3 h as above in fresh methionine-free media. Labeled cells calcium MEM and injected s.c. at a level of 1 x IO6 cells/mouse. In were washed twice in cold phosphate-buffered saline, lysed on ice for order to examine lung colonization potential, 5 x 10s cells/mouse were 20-30 min, precleared with 50% protein A-Sepharose, and subjected injected i.v.
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