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Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular
J L Dean1, A K McClendon, K R Stengel
1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract:
The retinoblastoma tumor suppressor, RB, is a key regulator of cellular proliferation that is functionally inactivated at high frequency in human cancer. Although RB has been extensively studied with regard to tumor etiology, loss of tumor-suppressor function often occurs relatively late in tumor progression. Therefore, inactivation of RB could have a profound impact on the behavior of tumors driven by discrete oncogenes. Here, collaboration between Ras or c-Myc deregulation and RB functional state was investigated in a model of conditional genetic deletion to decipher the effects related to disease progression. These studies showed that RB loss had a robust impact on mitogen dependence, anchorage dependence and overall survival, which was significantly modified by oncogene activation. Specifically, RB deficiency predisposed c-Myc-expressing cells to cell death and reduced overall tumorigenic proliferation. In contrast, RB deficiency exacerbated the tumorigenic behavior of Ras-transformed cells in both the model system and human tumor cell lines. As these tumors exhibited highly aggressive behavior, the possibility of exploiting the intrinsic sensitivity to cell death with RB loss was evaluated. Particularly, although Ras-transformed, RB-deficient cells bypassed the G1-checkpoint elicited by pharmacological activation of the p53 pathway, they were also highly sensitized to cell death. Altogether, these data suggest that the impact of RB deletion is dependent on the oncogene milieu, and can directly contribute to transformed phenotypes and response to therapeutic intervention.
Insights
Retinoblastoma tumor suppressor (RB) loss impacts cancer progression differently depending on oncogene activation. RB deficiency promotes Ras-driven tumors but sensitizes c-Myc-driven cells to cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The retinoblastoma tumor suppressor (RB) is crucial for regulating cell proliferation and is frequently inactivated in human cancers.
- RB inactivation often occurs late in tumor progression, suggesting its loss can significantly alter the behavior of established oncogene-driven tumors.
Purpose of the Study:
- To investigate the collaborative effects of Ras or c-Myc oncogene deregulation and RB functional status on tumor progression.
- To determine how RB loss influences cancer cell behavior, including proliferation, dependence on growth signals, and survival, in the context of specific oncogenes.
Main Methods:
- Utilized a conditional genetic deletion model to study the functional interplay between RB and oncogenes (Ras, c-Myc).
- Assessed mitogen and anchorage dependence, overall survival, and cell death sensitivity in RB-deficient and RB-proficient cells with varying oncogene activation.
- Evaluated the response of Ras-transformed, RB-deficient cells to p53 pathway activation and cell death induction.
Main Results:
- RB loss significantly impacted mitogen dependence, anchorage dependence, and survival, with effects modulated by oncogene activation.
- RB deficiency led to cell death and reduced proliferation in c-Myc-expressing cells.
- Conversely, RB deficiency exacerbated tumorigenic behavior in Ras-transformed cells, increasing aggressiveness.
- Ras-transformed, RB-deficient cells, despite bypassing G1-checkpoint control, showed heightened sensitivity to cell death.
Conclusions:
- The impact of RB deletion on cancer progression is context-dependent, varying with the specific oncogene milieu.
- RB inactivation can directly contribute to transformed phenotypes and influence a tumor's response to therapeutic interventions.
- Targeting cell death pathways may be a viable strategy for treating Ras-driven tumors with RB loss.
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