Expression of <i>bcl</i>‐2 oncogene protein is prevalent in small cell lung carcinomas

Jiang, Shi‐Xu; Sato, Yuichi; Kuwao, Sadahito; Kameya, Toru

doi:10.1002/path.1711770206

Cited by 160 publications

(87 citation statements)

References 23 publications

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“…Of interest was the strong bcl-2 staining in the three neuroendocrine tumours (two small-cell and one large-cell type), which were associated with high cell-loss factors, and one lesion of clear cell carcinoma. The overexpression of bcl-2 in small-cell carcinomas seems contradictory in a tumour characterized by prominent apoptosis and a high cell loss factor but frequent overexpression of bcl-2 in lung small-cell carcinoma has already been reported (Ben-Ezra et al, 1994;Jiang et al, 1995).…”

Section: Discussionmentioning

confidence: 98%

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Kennedy

Lamb²,

King³

et al. 1997

Br J Cancer

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Summary Immunohistochemical staining of bcl-2 and p53 proteins was compared with thymidine labelling index (TLI) and cell loss factor (0) in lung cancer. Neither bcl-2 nor p53 overexpression was associated with high cell loss but strong bcl-2 staining was associated with higher TLI. Concomitant strong p53 and bcl-2 expression, not the usual inverse relationship, plus high cell-loss factor was present in three neuroendocrine carcinomas. Other factors presumably have a role in controlling cell death in these tumours.Keywords: lung carcinoma; neuroendocrine; thymidine labelling index; cell loss factor; bcl-2; p53; apoptosis; immunohistochemistry Apoptosis is a major mechanism of tumour cell loss, itself a major determinant of tumour growth rate, and the protein products of both the p53 and bcl-2 genes have a role in this process. The functions of both these genes and their relationship to other regulatory proteins has been extensively reviewed (Lane, 1993;Piepentol and Vogelstein, 1993;Lu et al, 1996;Yang and Korsmeyer, 1996).In an earlier study (Kerr and Lamb, 1984), we derived data on cell proliferation and cell loss in 17 human lung tumours. Tumour thymidine labelling index (TLI) was measured in vitro and, using recognized methods and formulae (Collins et al, 1956; Steel 1967), a cell loss factor (0) was calculated. Cell loss factor expresses the proportion of cells being lost from a population relative to the number being added to it by mitotic activity. Thus a cell loss factor of 0.90 implies that for every 100 cells being added to a population by mitosis, 90 are lost by whatever means.In this study, we investigate the relationship between the cell proliferation/loss data in these 17 human lung tumours and their expression of the p53 and bcl-2 genes assessed immunohistochemically. MATERIALS AND METHODSThe histological classification of the tumours required revision of the original (Kerr and Lamb, 1984). 'Large-cell carcinoma with stratification' is now classified as poorly differentiated squamous carcinoma. One tumour, thought originally to be a metastatic deposit of large-cell carcinoma, now, with follow-up, fulfils criteria of a primary large-cell neuroendocrine cancer. Thirteen of the cases were typical bronchogenic carcinomas (six squamous, three adenocarcinoma, two small-cell undifferentiated, one largecell neuroendocrine and one large-cell undifferentiated carcinoma). Two were renal cell carcinoma metastases and one a primary clear cell carcinoma.Tumour thymidine labelling index (TLI) was obtained by in vitro incubation of tumour fragments with tritiated thymidine

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Section: Discussionmentioning

confidence: 98%

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Kennedy

Lamb²,

King³

et al. 1997

Br J Cancer

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“…10) and of BCL-2 ($40% patients; refs. 11,12). Commonly recurring, druggable oncogenic drivers are elusive, although mutually exclusive mutations are observed in genes within the PI3K pathway (36% of patients; ref.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, identifying novel anticancer strategies for SCLC treatment remains challenging. Given the commonly observed upregulation of BCL-2 in SCLC (11,12), one rational combination therapy under investigation is combining BCL-2 family apoptosis regulators with PI3K/mTOR survival signal inhibitors (14,15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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“…Enhanced Bcl-2 expression in these tumors not only permits cell growth and survival in the presence of cellular apoptotic signals associated with the transformed phenotype, but increased Bcl-2 can also lead to failure of chemotherapeutic strategies (2)(3)(4)(5)(6)(7)(8)(9)(10). Bcl-2 is the founding member of a family of proteins that contain one or more Bcl-2 homology (BH) domains (11).…”

Section: Introductionmentioning

confidence: 99%

Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

Tahir

Wass

Joseph

et al. 2010

Molecular Cancer Therapeutics

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ABT-263 inhibits the antiapoptotic proteins Bcl-2, Bcl-x L , and Bcl-w and has single-agent efficacy in numerous small cell lung carcinoma (SCLC) and leukemia/lymphoma cell lines in vitro and in vivo. It is currently in clinical trials for treating patients with SCLC and various leukemia/lymphomas. Identification of predictive markers for response will benefit the clinical development of ABT-263. We identified the expression of Bcl-2 family genes that correlated best with sensitivity to ABT-263 in a panel of 36 SCLC and 31 leukemia/ lymphoma cell lines. In cells sensitive to ABT-

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Expression of bcl‐2 oncogene protein is prevalent in small cell lung carcinomas

Cited by 160 publications

References 23 publications

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines

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