Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

/pdf/live-or-let-die-the-cell-s-response-to-p53-3v8en5zmb2.pdf

Live or let die: the cell's response to p53

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

/pdf/senescence-and-tumour-clearance-is-triggered-by-p53-55nfmgwcen.pdf

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

p53 is best known as a tumour suppressor, although recent studies have challenged the view that this is its only role. Instead, p53 has important functions in organismal development, and might contribute to a number of diseases other than cancer.

p53 in health and disease.

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.

/pdf/tp53-mutations-in-human-cancers-origins-consequences-and-3yze3radrd.pdf

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

/pdf/restoration-of-the-tumor-suppressor-function-to-mutant-p53-k0uluz3m5o.pdf

Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs

Purpose of the study: differential diagnosis of tumors arising from the mediastinum, as well as the analysis of the biological potential of the tumor, taking into account the relatively low incidence of these tumors among the population.Material and Methods. Macroscopic and microscopic examinations of the surgical specimen were performed using routine H&E staining. Immunohistochemical staining of paraffin-embedded tissue sections was performed using a Roche Ventana BenchMark Ultra system. The results obtained were evaluated taking into account the available literature data published on this nosology.Description. We present a rare case of a benign neoplasm of the thymus, lipofibroadenoma (LFA), which was localized in the left pleural cavity and originated from the anterior mediastinum with partial compression of the lower lobe of the left lung in a 59-year-old man. The tumor was revealed during a routine medical examination. The patient underwent left-sided thoracotomy with complete excision of the tumor and anterior mediastinal lymph node dissection. Macroscopic examination reveled that the tumor was predominantly composed of adipose tissue with fibrous layers. Histological examination showed a tumor composed of mature adipocytes of various sizes, among which remnants of the thymus with Hassal’s bodies and small number of lymphocytes and calcifications were found. Areas of fibrous stroma predominated over narrow strands of anastomosing epithelial cells with clear nuclei. Epitheliocytes formed slit-like structures infiltrated with lymphocytes, resembling the structure of breast fibroadenoma. Immunohistochemical examination revealed that epithelial cells were positive for PanKeratin and CK19, lymphocytes were positive for CD3 and CD20, and thymic cells expressed TdT. In this case, the neoplasm was almost asymptomatic, in contrast to previously published observations, which described an association with erythrocyte aplasia.Conclusion. Considering the clinical, histological and immunohistochemical data, it was feasible to make a differential diagnosis of the neoplasm and determine the histological type of the tumor as lipofibroadenoma. 

/pdf/a-rare-case-of-thymus-lipofbroadenoma-1fcmk95b.pdf

A rare case of thymus lipofbroadenoma

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Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs

A rare case of thymus lipofbroadenoma