Li Fraumeni syndrome, cancer and senescence: a new hypothesis

Pantziarka, Pan

doi:10.1186/1475-2867-13-35

Cited by 9 publications

(10 citation statements)

References 40 publications

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“…Half of individuals with LFS develop at least one LFS-associated cancer by age 30 and 15% to 35% of cancer survivors with LFS will develop multiple primary tumors over their lifetimes (34). It has also been proposed that patients with LFS have deregulated metabolism, including increased oxidative stress and hypoxia, to provide a microenvironment conducive to tumor formation, which can be one complication of dysfunctional p53 for these patients (35). Breast cancer is the most common type of cancer in women with LFS and the majority of tumors are ER þ (36).…”

Section: Li-fraumeni Syndromementioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E 2 , inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. Cancer Res; 75(23); 5001-7. Ó2015 AACR.

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Section: Li-fraumeni Syndromementioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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“…It has previously been proposed that cancer initiation in LFS is related to this ‘two compartment model’ of tumour metabolism [ 101 ]. Briefly, p53 signalling in response to increased oxidative stress can trigger cellular autophagy in fibroblastic cells, shifting their metabolism towards glycolysis.…”

Section: Tp53 and The Pre-cancerous Nichementioning

confidence: 99%

Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche

Pantziarka¹

2015

ecancer

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The complex relationship between tumour and stroma is still being elucidated but it is clear that cancer is a disease of more than just malignant cells. However, the dominant focus of our current understanding of Li Fraumeni Syndrome (LFS) remains on the function of p53 as ‘guardian of the genome’. Recent evidence shows that the TP53 gene is at the nexus of a wider range of functions, including aspects of cellular metabolism, aging and immunity. Incorporating this broader picture of the role of TP53 together with our understanding of the role of the host microenvironment in cancer initiation and progression gives a more nuanced picture of LFS. Furthermore, there is clinical evidence to suggest that the host environment in healthy individuals with LFS already includes some of the features of a ‘pre-cancerous niche’ that makes cancer initiation more likely. It is suggested, finally, that there are pharmacological interventions capable of altering this pre-cancerous niche, thus potentially reducing the cancer risk in individuals with LFS.

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“…Cells from LFS sufferers are known to exhibit telomere dysfunction, genomic instability, and spontaneous immortalization. Pantziarka () hypothesized that these features are evidences that the host microenvironment is “primed” for carcinogenesis over and above the lack of TP53 tumor suppressor function. Further, the “two‐compartment tumor metabolism” hypothesis, a new paradigm that describes a metabolic shuttle between autophagic cells in the tumor stroma and tumor cells, was proposed.…”

Section: Tp53 Mutants and Li–fraumeni Syndromementioning

confidence: 99%

TP53 Mutants in the Tower of Babel of Cancer Progression

et al. 2014

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Loss-of-function, partial-function, alteredfunction, dominant-negative, temperature sensitive, interfering, contact, structural, unfolded, misfolded, dimeric, monomeric, non-cooperative, unstable, supertrans, superstable, intragenic suppressor. TP53 mutants are many, more than 2,000 in fact, and they can be very diverse. Sporadic; germline; gain-of-function (GoF); oncogenic; rebel-angel; yin and yang; prion-like; metastasis-inducer; mediator of chemo-resistance; modifier of stemness. TP53 mutants can impact important cancer clinical variables, in multiple, often subtle ways, as revealed by cell-based assays as well as animal models. Here, we review studies investigating TP53 mutants for their effect on sequencespecific transactivation function, and especially recent findings on how TP53 mutants can exhibit GoF properties. We also review reports on TP53 mutants' impact on cancer cell transcriptomes and studies with Li-Fraumeni patients trying to classify and predict phenotypes in relation to experimentally determined transcription fingerprints. Finally, we provide an example of the complexity of correlating TP53 mutant functionality to clinical variables in sporadic cancer patients. Conflicting results and limitations of experimental approaches notwithstanding, the study of TP53 mutants has provided a rich body of knowledge, mostly available in the public domain and accessible through databases, which is beginning to impact cancer intervention strategies.

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Li Fraumeni syndrome, cancer and senescence: a new hypothesis

Cited by 9 publications

References 40 publications

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche

TP53 Mutants in the Tower of Babel of Cancer Progression

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