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Bax protein inhibits the anti-apoptotic actions of bcl-2. Loss of function mutations have been identified in several human tumors, and knockout of the bax gene results in tumorigenesis in mice, suggesting that bax acts as a classic tumor suppressor gene in vivo. The tumor suppressor gene p53 is a direct transcriptional activator of the bax gene, thus linking tumor suppression to apoptosis. Since mutated p53 gene correlates with the presence of immunoreactive p53 protein in tissues, there is often an inverse association between p53 and bax expression within the same tumor. In colorectal cancers occurring on the background of microsatellite instability (both sporadic as well as in the hereditary nonpolyposis colon carcinoma syndrome) bax mutations are present in the majority of tumors.
An immunohistochemical antibody is now available for assessment of bax levels in routinely fixed archival tissues. In keeping with its role as a tumor suppressor protein, loss of bax expression is associated with a variety of adverse prognostic factors such as advanced stage, lymph node metastasis, poor response to radio- and chemotherapy, and reduced disease-free and overall survival in colorectal, breast, head and neck, prostate and gynecological malignancies. Recent data has focused on simultaneously examining two apoptosis-related proteins - bcl-2 and bax - and expressing the intratumoral bcl-2:bax levels as a ratio; several lines of evidence suggest that the bcl-2:bax expression ratio is a better discriminant of prognosis than levels of any one protein alone. For example, bcl-2:bax expression ratios < 1 are associated with a survival advantage in ovarian carcinomas. Conversely, in prostate cancers, high bcl-2:bax ratios are associated with significantly poorer response to radiotherapy and therapy-failure. Finally, in head and neck squamous carcinomas, the bcl-2:bax ratio has been shown to be the strongest independent prognostic parameter in multivariate analysis.
Veripath OncoDiagnostics offers the facility to assess bcl-2 and bax simultaneously in solid tumors, and determine bcl-2:bax expression ratios for prospective and retrospective studies, as well as risk stratification. Bax is also offered as part of the standard gynecologic malignancy panels, but it can be ordered individually for any solid tumor. Currently, we are using an automated image analysis system to quantitatively score percentage positivity and intensity grade for bax and bcl-2 finally reflected in a histoscore on each evaluation. For more information contact Dr Raheela Ashfaq at Veripath OncoDiagnostics at 214.645.7053 or Raheela.Ashfaq@UTSouthwestern.edu.
Selected references:
1. Bakelendt M et al. Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer. J Clin Oncol 18:3775; 2000
2. Harima Y et al. Bax and bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIB cervical carcinoma. Cancer 88:132; 2000
3. Ito T et al. Decreased expression of bax is correlated with poor prognosis in oral and oropharyngeal carcinoma. Cancer Lett 140:81; 1999
4. Lohmann CM et al. Bcl-2:bax and bcl-2:bcl-x ratios by image cytometric quantitation of immunohistochemical expression in ovarian carcinoma: correlation with prognosis. Cytometry 42:61; 2000
5. Mackey TJ et al. Bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer.
6. Sturm I et al. Analysis of the p53/bax pathway in colorectal cancer: low bax is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 17:1364; 1999
7. Xie X et al. The prognostic value of spontaneous apoptosis, bax, bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer 86:913; 1999
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