Elsevier

Human Pathology

Volume 28, Issue 10, October 1997, Pages 1189-1195
Human Pathology

Original contribution
The role of p53, p21WAF1/C1P1, and bcl-2 in radioresistant colorectal carcinoma

https://doi.org/10.1016/S0046-8177(97)90257-4Get rights and content

Abstract

Genetic alterations in the p53 tumor suppressor gene are common in human colorectal cancers, occurring in approximately 70% of tumors. In vitro studies have shown that wild-type p53 is involved in controlling cell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemotherapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory protein, p21WAF1/C1P1 protein, and transcriptionally repress the bcl-2 gene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21WAF1/C1P1 and bcl-2 proteins in human colorectal cancers treated with radiation therapy, we examined the expression of these proteins by immunohistochemistry in pre-irradiated biopsy specimens and surgical specimens with residual tumor of 27 patients with colorectal carcinoma. Cell proliferation was measured using Ki-67 expression in the tumor cells. The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and in 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 protein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cells in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) of post-irradiated samples. p21WAF1/C1P1 expression was detected in 14 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of post-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21WAF1/C1P1 was expressed in most nonproliferating Ki-67—negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67—positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21WAF1/C1P1 expression was observed in normal colorectal mucosa and adjacent adenomatous mucosa. After radiation therapy, p53 protein accumulation did not change among residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increase, and five cases had a substantial decrease of p53 expression. Aberrant bcl-2 expression is not correlated with expression of p53 and does not increase significantly in post-irradiated tumor cells. p21WAF1/C1P1 expression is markedly reduced in tumor cells that survive radiation therapy.

References (40)

  • AJ Levine

    The tumor suppressor genes

    Ann Rev Biochem

    (1993)
  • LH Hartwell et al.

    Cell cycle control and cancer

    Science

    (1994)
  • SN Powell et al.

    Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitivity and override of G2 delay

    Cancer Res

    (1995)
  • RS Paules et al.

    Defective G2 checkpoint function in cells from individuals with familial cancer syndromes

    Cancer Res

    (1995)
  • KJ Russell et al.

    Abrogation of the G2 checkpoint results in differential radiosensitivity of G1 checkpoint-deficient and G1 checkpoint-deficient competent cells

    Cancer Res

    (1995)
  • WS El-Deiry et al.

    WAF1/C1PI is induced in p53 mediated G1 arrest and apoptosis

    Cancer Res

    (1994)
  • Y Tsujimoto et al.

    Analysis of the structure, transcripts and protein products of bcl-2, the gene involved in human follicular lymphoma

  • Y Wang et al.

    Wild-type p53 triggered apoptosis is inhibited by bcl-2 in v-myc induced T cell Lymphomas

    Oncogene

    (1993)
  • JC Reed et al.

    Differential expression of bcl-2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin

    Cancer Res

    (1991)
  • F Pezzella et al.

    bcl-2 protein in non-small cell lung carcinoma

    N Engl J Med

    (1993)
  • Cited by (41)

    • Colonic crypt changes during adenoma development in familial adenomatous polyposis: Immunohistochemical evidence for expansion of the crypt base cell population

      2004, American Journal of Pathology
      Citation Excerpt :

      Like FAP adenomas, in the development of sporadic colon cancers, a mutation in the second APC allele usually occurs by the adenomatous polyp stage, and complete inactivation of wild-type APC occurs in the majority of colorectal carcinomas.48 In sporadic CRC6,7,9 as in our FAP adenomatous crypts, there was an increase in the proportion of total neoplastic epithelial cells staining for Bcl-2, survivin, and Ki-67 compared to normal colonic mucosa. Colon carcinomas are reported to contain fewer cells expressing p21WAF1/C1P1 and p27kip1 than normal epithelium,13,14,49 and we observed only a slight increase in the proportion of p21WAF1/C1P1- and p27kip1-stained cells in FAP adenomas.

    • Radiation-associated changes in tissues and tumours

      2003, Current Diagnostic Pathology
    View all citing articles on Scopus
    View full text