Paradoxical role of apoptosis in tumor progression

Gurova, Katerina V.; Gudkov, Andrei V.

doi:10.1002/jcb.10382

Cited by 45 publications

(24 citation statements)

References 34 publications

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“…The prime determinant of the dormant state proves not to be a limited immortal (stem cell) composition per se, but to a limited ability of stem cells to migrate, coupled, curiously, with a limited death rate and excess replicative potential among the nonstem cells. This finding corroborates recent observations of an inverse dependence between these factors and malignant progression (8,9).…”

Section: Introductionsupporting

confidence: 93%

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

et al. 2009

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Even after a tumor is established, it can early on enter a state of dormancy marked by balanced cell proliferation and cell death. Disturbances to this equilibrium may affect cancer risk, as they may cause the eventual lifetime clinical presentation of a tumor that might otherwise have remained asymptomatic. Previously, we showed that cell death, proliferation, and migration can play a role in shifting this dynamic, making the understanding of their combined influence on tumor development essential. We developed an individual cell-based computer model of the interaction of cancer stem cells and their nonstem progeny to study early tumor dynamics. Simulations of tumor growth show that three basic components of tumor growth-cell proliferation, migration, and death-combine in unexpected ways to control tumor progression and, thus, clinical cancer risk. We show that increased proliferation capacity in nonstem tumor cells and limited cell migration overall lead to space constraints that inhibit proliferation and tumor growth. By contrast, increasing the rate of cell death produces the expected tumor size reduction in the short term, but results ultimately in paradoxical accelerated long-term growth owing to the liberation of cancer stem cells and formation of self-metastases.

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Section: Introductionsupporting

confidence: 93%

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

et al. 2009

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“…For example, in a murine model of c-mycinduced B cell lymphoma, Bcl-2 expression abrogated the selective pressure(s) needed to lose p53 and prevented the formation of aneuploid cells [8]. Similar observations with regard to Bcl-2 were also observed in other models [9]. In contrast, increased Bax (Lck-Bax38/1) was associated with accelerated tumor formation in both p53 +/+ and p53 −/− mice [4,10].…”

Section: Introductionmentioning

confidence: 65%

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Wetering

Coleman

Spitz

et al. 2008

Free Radical Biology and Medicine

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Increased reactive oxygen species (ROS) such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady state levels of key antioxidant enzymes with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic mouse models. We examined the impact of MnSOD expression in the development of T cell lymphoma in mice expressing proapoptotic Bax. Lck-Bax38/1 transgenic mice were crossed to mice overexpressing MnSOD (LckMnSOD) as well as MnSOD +/− mice. The effect of MnSOD on apoptosis, cell cycle, chromosomal instability (CIN), and lymphoma development was determined. The apoptotic and cell cycle phenotypes observed in thymocytes from control and Bax transgenic mice were unaffected by variations in MnSOD levels. Remarkably, increased gene dosage of MnSOD significantly decreased aneuploidy in pre-malignant thymocytes as well as the onset of tumor formation in Lck-Bax38/1 mice. The observed effects of MnSOD support a role for ROS in CIN and tumor formation in this mouse model of T cell lymphoma.

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“…It has also been suggested that adenomatous growth and tumor invasion are two different phases of tumor progression, and it may be during the later phase of tumor invasion, when the apoptotic stresses are different, that selection of a different means of inhibition of apoptosis (such as p53 dependency) occurs [31,32,41]. Furthermore, Gurova and Gudkov [42] recently reviewed studies related to the paradoxical role of apoptosis in tumor progression and concluded that inhibition of apoptosis does not lead to loss of genomic stability but rather creates a tumor environment that no longer supports further tumor progression. Therefore, inhibitors of apoptosis can be considered as factors suppressing tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Recurrence and survival predictive value of phenotypic expression of Bcl-2 varies with tumor stage of colorectal adenocarcinoma

Chatla

Jhala

Katkoori

et al. 2005

CBM

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Although decreased or lack of expression of Bcl-2 has been correlated with advanced tumor stage and shortened patient survival in colorectal cancer (CRC), its value in predicting the recurrence has not been well explored. Therefore, we assessed the usefulness of phenotypic expression of Bcl-2 in non-Hispanic Caucasian patients with CRCs in identifying risk of recurrence. Archival tissues of 92 Stage II and 66 Stage III primary CRCs were evaluated for immunohistochemical expression of Bcl-2. None of these patients received either pre-or post-surgical adjuvant therapies. Kaplan-Meier and Cox proportional hazards methods were used to estimate the rates of recurrence and survival according to Bcl-2 expression. Decreased expression of Bcl-2 was associated with an increased rate of recurrence in patients with Stage II CRCs (5-year log-rank test P = 0.0015; Hazard-Ratio (HR) = 3.90, 95%C.I.: 1.55-9.77) but not with Stage III CRCs (5-year log-rank test P =0.6058; HR =1.07, 95%C.I.: 0.47-2.45) after adjusting for other demographic and clinicopathological features. Furthermore, decreased expression of Bcl-2 was an indicator of short survival in patients with Stage II CRCs but not with Stage III CRCs. Thus, decreased or lack of Bcl-2 expression in primary CRCs may serve as a molecular biomarker of high risk of recurrence for Caucasian patients with Stage II CRCs. These findings might be useful in identifying biologically aggressive phenotypes of Stage II CRCs, and may aid the oncologist in designing maximally appropriate therapeutic regimens.

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Paradoxical role of apoptosis in tumor progression

Cited by 45 publications

References 34 publications

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics

Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma

Recurrence and survival predictive value of phenotypic expression of Bcl-2 varies with tumor stage of colorectal adenocarcinoma

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