Correlation of apoptosis with tumour cell differentiation, progression, and HPV infection in cervical carcinoma.

Shoji, Yasuhiro; Saegusa, Makoto; Takano, Yoshinao; Ohbu, Makoto; Okayasu, Isao

doi:10.1136/jcp.49.2.134

Cited by 57 publications

(46 citation statements)

References 32 publications

(4 reference statements)

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“…In a previous study, we noted that the majority of Bcl-2-negative invasive tumours were accompanied by Bcl-2-negative DCIS (H-J. van (Lipponen and Aaltomaa, 1994;Aihara et al, 1995;Du et al, 1996;Isacson et al, 1996;Koshida et al, 1996;Shoji et al, 1996). For instance, in gastric cancer, Bcl-2 expression was positively correlated with a low Al and MI, whereas Bax expression seemed to be correlated with an increased AI and MI.…”

Section: Resultsmentioning

confidence: 99%

Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity

Slooten

Vijver²,

Velde³

et al. 1998

Br J Cancer

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Summary Bcl-2 has been demonstrated to inhibit apoptosis in breast cancer cells in vitro, and the ratio between Bcl-2 and its proapoptotic homologue Bax seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl-2 and the rate of apoptotic and necrotic cell death in breast tumours. From a series of 441 premenopausal, lymphnode-negative breast cancer patients, a subset of 49 tumours was selected in which immunostaining for the 26-kDa isoform of Bcl-2 was either absent (n = 23) or very high (n = 26). High expression of Bcl-2 was found to be strongly associated with low rates of apoptotic (P < 0.001) and necrotic cell death (P < 0.001). The mean value of the apoptotic index was 2.69% ± 1.40% in Bcl-2-negative tumours and 0.68% ± 1.00% in Bcl-2-positive tumours. Expression of the proapoptotic protein Bax correlated neither with Bcl-2 nor with the frequency of apoptotic cells. Immunostaining for the antiapoptotic Bcl-2 homologue Bcl-XL correlated with Bcl-2 expression (P < 0.001) but not with apoptosis. High proliferation rate and high tumour grade (Bloom-Richardson) were strongly associated with absence of Bcl-2 expression (P < 0.001). p53 accumulation was associated with absence of Bcl-2 expression and increased apoptotic activity. Loss of Bcl-2 expression was strongly correlated with increased apoptotic and necrotic cell death, high proliferation rate and high tumour grade, supporting a model in which Bcl-2 not only mediates cell death, but also cell division in breast cancer tissue, and in which regulation of cell division and cell death are tightly linked.

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Section: Resultsmentioning

confidence: 99%

Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity

Slooten

Vijver²,

Velde³

et al. 1998

Br J Cancer

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“…In the present study, the possibility was excluded by comparing the TllNEL-positive cells with histological findings, including inflammation in H&E-stained sections. p53, HPV and apoptosis in oral carcinorma 359 various locations, which ranged from 1.5 to 10.9 (Kasagi et al, 1994;Shoji et al, 1996;Tatebe et al, 1996). In relation to p53 status, SCCs associated with p53 mutation had significantly lower Al than those with wild-type p53 (Table 3).…”

Section: Discussionmentioning

confidence: 99%

p53 mutations and human papillomavirus DNA in oral squamous cell carcinoma: correlation with apoptosis

Koh

Cho²,

Kong³

et al. 1998

Br J Cancer

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Summary Forty-two oral squamous cell carcinomas (SCCs) were analysed for p53 mutations and human papillomavirus (HPV) (Regezi et al. 1993). W'hereas the epidemiology has been w-ell described so far. the molecular steps involsed in the pathogenesis of these common neoplasms are poorly understood. The role of human papillomas-irus (HPV) in the development of anogenital cancers has been widely studied. and current evidence shows that HPV infection is necessars for the desvelopment of most cervical cancers (zur Hausen. 1994). Approximately 80-90% of cervical carcinomas contain HPV DNA. and the predominant or high-risk types appear to be HPV-16. -18 and -33 (Yoshikawa et al. 1991). HPV E6 and E7 proteins. consistentlv expressed in HPV-transformed and HPVpositive tumours. can exert their oncogenic potential bv inactivating the products of the p53 tumour-suppressor cene (Lemine. 1990: zur Hausen. 1994) and the retimoblastoma (Rb) grene (Dy-son et al. 1989). In oral malignant lesions. the state of HPV infection has been reported to be as high as 76%c (Snijders et al. 1994). although there are still conflicting results in infection rate and role of HPV in oral carcinorenesis.

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“…Thus, in vitro experiments demonstrating apoptosis and IL-1a release from keratinocytes expressing high levels of E6 and E7 genes from retroviral vectors may be biologically relevant and representative of HSIL or carcinoma where E6 and E7 genes are integrated and transcriptionally upregulated (DuÈ rst et al, 1992;Stoler et al, 1992). Previous studies have shown that apoptosis is increased in HSIL and cervical carcinoma (Isacson et al, 1996;Shoji et al, 1996) and correlates with increased cellular proliferation rather than with`low or high risk' HPV types (Isacson et al, 1996). Our results con®rm these observations and extend them by suggesting that the extent of apoptosis is related to levels of HPV RNA expression.…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

et al. 1998

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Interleukin-1a (IL-1a) is a multifunctional cytokine that promotes in¯ammation, tissue remodeling and epithelial hyperplasia. Keratinocytes produce and sequester large amounts of biologically active IL-1a which can be released after injury or infection. We show that high level expression of human papillomavirus (HPV) type 16 E6 and E7 oncoproteins enhanced release of IL-1a from cultures of normal cervical keratinocytes (relative eectiveness E74E6/E7>E64 control). The amount of IL-1a released was directly related to the ability of E7 or E6/E7 to stimulate apoptosis. E7 proteins that bound the retinoblastoma protein (Rb) strongly (HPV-16 and -18) induced more IL-1a release than those that bound poorly (HPV-6 and an HPV-16 E7 24gly mutant). Furthermore, overexpression of the E2F-1 transcription factor, a downstream target of Rb, induced extensive apoptosis and IL-1a release. Apoptosis and IL-1a release in response to growth factor removal occurred in part through a p53-independent pathway as coexpression of E6 and downregulation of p53 did not prevent either response. Immunohistochemical analyses showed that IL1a was expressed by keratinocytes in normal cervical epithelia, low and high grade dysplasias, and cervical carcinomas. However, HPV-16 E6/E7 RNA expression and apoptosis increased in parallel in proliferating keratinocytes in severe dysplasias and carcinomas suggesting that IL-1a release is associated with progression to high grade disease. Thus, high level expression of the HPV-16 E7 protein sensitizes keratinocytes to apoptosis which results in release of IL-1a.

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Correlation of apoptosis with tumour cell differentiation, progression, and HPV infection in cervical carcinoma.

Abstract: Aims-To clarify the significance of apoptosis in the progression of uterine cervical neoplasias, including cervical intraepithelial neoplasia (CIN), microinvasive carcinoma (MIC), and invasive squamous cell carcinoma (ISCC)

Cited by 57 publications

References 32 publications

Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity

Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity

p53 mutations and human papillomavirus DNA in oral squamous cell carcinoma: correlation with apoptosis

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

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