Bcl-2

Proteins of the Bcl-2 family are regulators of apoptosis (programmed cell death) localized to membranes of primarily mitochondria, but also to smooth endoplasmic reticulum and nucleolemma. The fine balance between pro- and anti-apoptotic Bcl-2 family members regulates the cell fate in response to many signalling pathways. Altered expression of the proteins may lead to either premature cell death or to inappropriate cell survival promoting neoplastic growth. Bcl-2, Bax and Bcl-X are the most well known proteins in this family. Bcl-2 ("B-cell lymphoma/leukaemia-2"), which acts as an inhibitor of apoptosis, was originally discovered as a proto-oncogene in low-grade B-cell lymphomas. In the adult organism Bcl-2 expression is generally confined to cells that are rapidly dividing and differentiating. In lymphocytes, Bcl-2 is highly expressed in T-cells, pro-B cells and mature B-cells (where lifespan is extended) while downregulated in germinal centre B-cells (where apoptosis forms part of the developmental pathway in order to select only cells producing antibodies with high avidity). In neoplastic lesions Bcl-2 upregulation may act by suppression of programmed cell death and extension of the tumour cell life span. Bcl-2 overexpression contributes to increased resistance to chemotherapy. However, the prognostic value of Bcl-2 overexpression is dependent on the tumour type, and in some types BCl-2 may even have a tumour suppressor effect.

Overexpression of Bcl-2 is common in many types of cancer, including non-Hodgkin's lymphoma and leukaemias, adenocarcinomas (e.g., prostate, colorectum, stomach, and lung), squamous cell carcinoma, small cell carcinoma, neuroblastoma and various sarcomas. Among the latter, strong Bcl-2 positivity has particularly been demonstrated in gastrointestinal stromal tumor, solitary fibrous tumor, and synovial sarcoma, while fibromatosis and "malignant fibrous histiocytoma" are usually negative. Among malignant lymphomas, Bcl-2 protein overexpression is often caused by chromosomal translocation (14;18) with Bcl-2 gene rearrangement. This is especially seen in follicular lymphoma. bcl-2 is expressed in almost 100% of the grade I lymphomas, in >80% of the grade II and in 75% of the grade III lymphomas. Follicular lymphoma of the skin is often bcl-2 negative.

Bcl-2 is helpful in distinguishing follicular lymphoma from reactive follicular hyperplasia. Bcl-2 staining can not be used for differential diagnosis between follicular lymphoma and other types of low-grade B-cell lymphomas since most of the latter also express bcl-2. Monocytoid B-cell hyperplasia contrasts with bcl-2 negativity against positive reaction in 80% of the marginal zone lymphomas. Possibly, Bcl-2 may aid in the differential diagnosis of sarcomas (see above).

Tonsil is recommendable as positive and negative tissue control for BCL2. A moderate to strong, predominantly cytoplasmic staining reaction should be displayed in virtually all T-cells and B-cells in the mantle zone of the reactive follicles, whereas the majority of the basal squamous epithelial cells, e.g. lining the tonsillar crypts, must show an at least weak staining intensity. Germinal centre T-cells should be distinctively demonstrated, whereas germinal centre B-cells should be negative.

Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993;81:3091-6. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol 1998;16:395-419 Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003 Nov 24;22(53):8590-607. Review. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004 Jul 30;305(5684):626-9. Review. Heiser D, Labi V, Erlacher M, Villunger A. The Bcl-2 protein family and its role in the development of neoplastic disease. Exp Gerontol. 2004 Aug;39(8):1125-35. Review. Kirkin V, Joos S, Zornig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 2004 Mar 1;1644(2-3):229-49. Review. Lai R, Arber DA, Chang KL, Wilson CS, Weiss LM: Frequency of bcl-2 expression in non-Hodgkin’s lymphoma: a study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Modern Pathology 1998; 11:864-869. Misao J, Hayakawa Y, Ohno M, Kato S, Fujiwara T, Fujiwara H. Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation. 1996 Oct 1;94(7):1506-12. Ouyang YB, Giffard RG. Changes in astrocyte mitochondrial function with stress: effects of Bcl-2 family proteins. Neurochem Int. 2004 Jul-Aug;45(2-3):371-9. Review. Pezzella F, Gatter K. What is the value of bcl-2 protein detection for histopathologists? Histopathology 1995;26:89-93. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, et al. Bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 1993;329:690-4. Reed JC: Bcl-2 family proteins. Oncogene 1998; 17:3225-3236. Tsujimoto Y, Cossman J, Jaffe E et al.: Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985;228:1440-1443. West RB, Warnke RA, Natkunam Y. The usefulness of immunohistochemistry in the diagnosis of follicular lymphoma in bone marrow biopsy specimens. Am J Clin Pathol. 2002 Apr; 117(4): 636-43. Erratum in: Am J Clin Pathol 2002 Jul;118(1):145.