Tumorigenic Cells Are Common in Mouse MPNSTs but Their Frequency Depends upon Tumor Genotype and Assay Conditions

Buchstaller, Johanna; McKeever, Paul E.; Morrison, Sean J.

doi:10.1016/j.ccr.2011.12.027

Cited by 29 publications

(23 citation statements)

References 51 publications

(77 reference statements)

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“…Survival as well as tumor incidence was compared with C57BL/6, Cpt1c gt/gt and Nf1 þ / À : p53 þ / À mice (Figure 6a). Similar to previous reports, 19,20 we observed that Nf1 þ / À : p53 þ / À mice developed soft tissue sarcomas of the limbs and abdomen as well as lymphomas at around 3-6 months of age and with a penetrance of over 70%. CPT1C depletion in this murine tumor model highly increases the median survival time from 5-15 months (Po0.0001).…”

Section: Resultssupporting

confidence: 79%

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

et al. 2013

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Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors. Hypoxia is an important chronic stress on tumor cell growth and has been shown to correlate with poor disease-free and reduced overall survival in a variety of carcinomas and sarcomas. 1 To enhance survival in an altered environment such as hypoxia cancer cells undergo a so-called metabolic transformation. [2][3][4] The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells upregulate glycolysis to limit their energy consumption. However, there is increasing evidence that not only glucose metabolism, but also fatty acid oxidation (FAO) is involved in metabolic transformation. Although glucose seems to be the major energy source for tumor growth and survival, there is increasing evidence that alternative energy sources such as fatty acid metabolism are altered in cancer cells, even under hypoxic conditions. Indeed, fatty acid synthase has been found to be upregulated in many human cancers, 5 and inhibitors of the fatty acid synthase show antitumor activity. 6 As recently published, we identified carnitine palmitoyltransferase (CPT) 1C (CPT1C) as a potential novel p53-target gene. 7 By their restriction of fatty acid import into mitochondria, 4 the CPT 1 (CPT1) family of enzymes represent key regulatory factors of FAO. There are three tissue-specific isoforms of CPT1: CPT1A that is found in liver, CPT1B in muscle and CPT1C in brain and testes. Loss-of-function of CPT1C was generated in mouse embryonic stem cells (Cpt1c gt/gt ES cells). Importantly, Cpt1c gt/gt ES cells readily succumbed to cell death under hypoxic conditions, whereas control cells were resistant. ES cells deficient for CPT1C showed a spontaneous induction in...

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Section: Resultssupporting

confidence: 79%

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

et al. 2013

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“…In benign skin tumors, addition of stromal cells-either cancer-associated fibroblasts (CAFs) or endothelial cells (ECs)-is required for tumor propagation (44). Depending on the tumor genotypes, some malignant peripheral nerve sheath tumors require the addition of laminin for successful engraftment (45). These findings indicate that transplantation assays need to be adapted and optimized for each tumor subtype, possibly by cotransplantation of different components of the tumor stroma, such as CAFs or ECs, or by the addition of exogenous components of the CSC niche.…”

Section: Cancer Stem Cells In Solid Tumorsmentioning

confidence: 99%

Cancer Stem Cells: Basic Concepts and Therapeutic Implications

Nassar

Blanpain

2016

Annu. Rev. Pathol. Mech. Dis.

647

478

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Different mechanisms contribute to intratumor heterogeneity, including genetic mutations, the microenvironment, and the existence of subpopulations of cancer cells with increased renewal capacity and the ability to recapitulate the heterogeneity found in primary tumors, which are referred to as cancer stem cells (CSCs). In this review, we discuss how the concept of CSCs has been defined, what assays are currently used to define the functional properties of CSCs, what intrinsic and extrinsic mechanisms regulate CSC functions, how plastic CSCs are, and the importance of epithelial-to-mesenchymal transition in conferring CSC properties. Finally, we discuss the mechanisms by which CSCs may resist medical therapy and contribute to tumor relapse.

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“…We addressed this question in mouse models of malignant peripheral nerve sheath tumors (MPNSTs) (Buchstaller et al, 2011). We found that approximately 20% of mouse MPNST cells have the potential to form tumors, even when transplanted into fully immunocompetent mice.…”

Section: Tumorigenic Cells Are Abundant In Some Cancersmentioning

confidence: 99%

Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty

2012

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The differentiation of tumorigenic cancer stem cells into non-tumorigenic cancer cells confers heterogeneity to some cancers beyond that explained by clonal evolution or environmental differences. In such cancers, functional differences between tumorigenic and non-tumorigenic cells influence response to therapy and prognosis. However, it remains uncertain whether the model applies to many, or few, cancers due to questions about the robustness of cancer stem cell markers and the extent to which existing assays underestimate the frequency of tumorigenic cells. In cancers with rapid genetic change, reversible changes in cell states, or biological variability among patients the stem cell model may not be readily testable.

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Tumorigenic Cells Are Common in Mouse MPNSTs but Their Frequency Depends upon Tumor Genotype and Assay Conditions

Cited by 29 publications

References 51 publications

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

Cancer Stem Cells: Basic Concepts and Therapeutic Implications

Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty

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