p53: regular or super?

Increased p53 expression under the endogenous promoter protects "super p53" mice from tumorigenesis without the undesirable effects of premature aging.     

p63 and p73: teammates or adversaries?

In this issue of Cancer Cell, Kovacic and colleagues have reexamined the role of STAT1 in murine models of leukemogenesis. Their studies shed new light on the complex interplay between cell-autonomous contributions and host responsiveness to cancer and elucidate a previously unknown role of STAT1 in tumor progression.     

Repeat cytoreductive surgery (CRS) for recurrent colorectal peritoneal metastases: Yes or no?

Purpose

To clarify the role of repeat CRS for recurrent colorectal carcinoma (CRC) through: (i) Systematic review of the literature (ii) Analysis of survival outcomes in a prospective cohort.

Methods

(i) Pubmed and MEDLINE from 1980 to July 2013 searched using terms: colorectal carcinoma, peritonectomy, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), redo, repeat, and iterative. (ii) Kaplan–Meier Survival analysis of consecutive patients undergoing repeat CRS at St George Hospital between Jan 2000 and July 2013.

Results

(i) The search strategy yielded 309 articles, 5 meeting inclusion criteria, reporting on 91 patients. Median overall survival from first CRS ranged from 39 to 57.6 months with 3-yr survival of 50%, and 5-year survival of 30%. Median survival from second CRS was 20-months with 1-yr survivals of 72% and 66% and 2-year survivals of 50% and 44%. (ii) Repeat CRS performed on 18 patients found median survival from first CRS was 59 months, with 1, 3, and 5-year survival of 100%, 52% and 26% respectively. Median survival from repeat CRS was 22.6 months with 1, 2, and 3-year survival of 94%, 48% and 12% respectively.

Conclusion

The current data on repeat CRS in CRC is relatively immature and more data is required before drawing clear conclusions. Patient selection should be on a case by case basis conducted through a MDT process with emphasis on surrogate markers for favourable outcomes.     

Zoledronic acid and radiation: toxicity, synergy or radiosensitization?

Introduction

Zoledronic acid (Z) is a bisphosphonate used in hypercalcaemia-related cancer, in complications for bone metastasis and in postmenopausal osteoporosis and it has been related to osteoradionecrosis, especially when associated with radiation to the head and neck structures.

Objectives

To determine the radiosensitization capacity of zoledronic acid in the combined treatment with ionizing radiation (IR) by evaluating its genotoxic and cytotoxic capacities in non-tumoral cells.

Materials and methods

The genotoxic effect of Z was studied by means of the micronucleus test in cytokinesis-blocked cells of human lymphocytes irradiated before and after a 2 Gy irradiation, while the cytotoxic effect was studied by a cell viability test in the PNT2 cell line before and after exposure to different X-ray doses (0–20 Gy) in four groups (Z alone, radiation alone, Z + IR and IR + Z).

Results

A dose-dependent and time-dependent cytotoxic effect of Z and IR on PNT2 cells in vitro (p > 0.001) was demonstrated. With the concentrations recommended for humans, the combined treatment had a more pronounced effect than individual treatments (p < 0.001). The effect was synergic (CI < 1), increasing the Z enhancement ratio (2.6) and sensitization factor (56 %); the effect of Z was always greater after IR exposure. In the genotoxic effect, only the administration of Z after irradiation (IR + Z) increased chromosome damage (p < 0.001) and the sensibilization factor (35.7 %).

Conclusion

High concentrations of Z are toxic, but the concentrations recommended for clinical practice in humans give it the characteristics of a radiosensitization agent, whose effect is even greater when administered after IR.     

The limitless role of p53 in cell cycle machinery: good news or bad news?

The p53 tumor suppressor gene acts as a great protagonist in deciding how cells undergo either cell cycle arrest or apoptosis after experiencing various stress signals, including DNA damage, hypoxia, oncogene activation, and hyperproliferation. Research on p53 is in steady expansion, as evidenced by the continual flood of papers claiming novel mutations, gain or loss of p53 functions, and gene interactions. The latest study carried out by Spurgers of Texas University and his Colleagues (J Biol Chem 2006; 281:25134-42) emphasizes the strong impact of p53 in the complicated machinery that regulates cell cycle progression. In this paper, microarray data and well-evaluated statistical procedures on PC3 and LNCaP prostate carcinoma cells, open new perspectives in p53 mechanisms and bring the simultaneous identification of novel p53-repressed cell cycle genes, hopefully providing significant improvements in the study of DNA damage response, multistep carcinogenesis, and treatment rationales and outcomes.     

To die or not to die: how does p53 decide?

p53 is frequently mutated in cancer and as a result is one of the most intensely studied tumour suppressors. Analysis of the primitive forms of p53 found in Caenorhabditis elegans and Drosophila, alongside studies using transgenic mouse models, indicate that the induction of apoptosis is both the most conserved function of p53 and vital for tumour suppression. p53-mediated apoptosis occurs through a combination of mechanisms which include pathways that are both dependent and independent of alterations in gene expression. In response to genotoxic insult, these pathways probably act together, thereby amplifying the apoptotic signal. However, the picture is complicated because the p53 activity is determined by stress type and individual cellular characteristics. The numerous p53 responsive genes that have been identified also provide further means of controlling the actions of p53. The recent discoveries of proteins that interact with p53 and specifically regulate the ability of p53 to trigger apoptosis have provided further mechanistic insights into the role of p53 in inducing cell death. Understanding the molecular basis of the proapoptotic action of p53 can assist in our quest to reintroduce or reactivate p53 in human tumours.     

Mdm2's Dilemma: To Degrade or To Translate p53?

In this issue of Cancer Cell, Gajjar et al. provide insight into how Mdm2 can both inhibit and enhance p53 activity. In the basal setting, Mdm2 binds p53 and promotes p53 degradation. Under stress conditions, ATM-dependent phosphorylation of Mdm2 results in its recruitment to p53 mRNA, thereby stimulating p53 translation.     

Molecular markers in gastric cancer: can p53 and bcl-2 protein expressions be used as prognostic factors?

BACKGROUND: The prognostic value of p53 and bcl-2 protein expressions in gastric cancer is still unclear, as shown by the discordant results still reported in the literature. PATIENTS AND METHODS: In this study, p53 and bcl-2 protein expressions were investigated by immunohistochemistry and correlated with various clinicopathological parameters and survival, in a series of 52 gastric cancer patients who underwent potentially curative gastrectomy. RESULTS: p53 expression was observed in 34 patients (65.4%) and was significantly correlated with the intestinal type of cancer (p=0.018). Bcl-2 expression was detected in 12 patients (23.1%) and inversely correlated with lymph node metastasis (p=0.042) and tumour grade (p=0.024). There was a statistically significant inverse relationship between p53 and bcl-2 expression (p=0.014). Moreover, p53 and bcl-2 protein expressions had no significant influence on overall survival. CONCLUSION: These results suggest that the expression of p53 and bcl-2 proteins has no significant impact on the outcome of patients with gastric cancer.     

Inverted urothelial papilloma: is ploidy, MIB-1 proliferative activity, or p53 protein accumulation predictive of urothelial carcinoma?

BACKGROUND: Inverted urothelial papilloma is an unusual neoplasm of the urinary tract. Although the association between inverted urothelial papilloma and urothelial carcinoma is not entirely clear, many studies indicate that patients with inverted papilloma are at increased risk for the development of urothelial carcinoma. In addition, aneuploid inverted papillomas have been associated with the subsequent development of urothelial carcinoma. The objective of this study was to determine whether ploidy, MIB-1 proliferative activity, or p53 protein staining in inverted papilloma were predictive of urothelial carcinoma. METHODS: Fifty-one cases of inverted papilloma were retrieved from the Tissue Registry of the Mayo Clinic. Clinical records were reviewed for patient age, length of follow-up, and history of urothelial carcinoma (defined as carcinoma prior to, concurrent with, or subsequent to the diagnosis of inverted papilloma). DNA ploidy analysis was determined using Feulgen stained sections from paraffin embedded tissues using an image analysis system. Quantitation of MIB-1 proliferative activity and p53 immunostaining was determined similarly using immunoperoxidase stained sections from paraffin embedded tissues. RESULTS: The mean age at diagnosis of inverted papilloma was 63.9 years (range, 37-87 years), and there were 39 men and 12 women. Patients were followed for a mean of 56.5 months (range, 1-252 months). Tumors ranged in size from 0.2 to 4.3 cm (mean, 0.9 cm). Eight patients (15.7%) had a prior, concurrent, or subsequent noninvasive World Health Organization and International Society of Urologic Pathology (WHO/ISUP) papillary neoplasm of low malignant potential or papillary carcinoma of low grade (formerly WHO Grade 1 or 2 papillary urothelial carcinoma). Inverted papillomas in patients with a history of urothelial carcinoma were all diploid and had a mean MIB-1 activity of 6.3% (range, 0.04-24.8%) and mean p53 protein staining of 12.6% (range, 0.5-24.9%). These inverted papillomas ranged in size from 0.3 to 1.0 cm (mean, 0.5 cm). Inverted papillomas in patients without a history of urothelial carcinoma were aneuploid in 6 cases (14.3%) and diploid in the remaining cases. These inverted papillomas had a mean MIB-1 activity of 1.6% (range, 0.06-9.0%) and mean p53 protein staining of 9.7% (range, 0.05-38.0%). Tumor size ranged from 0.2 to 4.3 cm (mean, 1.0 cm). There were no statistically significant differences in MIB-1 activity, p53 protein staining, ploidy, and morphologic features between inverted papillomas in patients with and without a history of urothelial carcinoma. CONCLUSIONS: Ploidy, MIB-1 proliferative activity, and p53 immunostaining in inverted urothelial papilloma were not useful in identifying patients who had a history of urothelial carcinoma.     

HPV infection and p53 and p16 expression in esophageal cancer: are they prognostic factors?

Background

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignant tumor. Currently, Human papillomavirus (HPV) is suggested as a potential risk factor for esophageal cancer (EC) in addition to the classic risk factors, alcohol and tobacco, but this hypothesis still remains contradictory. We sought to investigate wether HPV and well-known biomarkers (p16 and p53) and patient-related factors that may have impact on survival of ESCC.

Methods

We conducted a prospective cohort study. By using multiplex PCR, we determined the prevalence of high risk HPV in ESCC, and evaluated the immunohistochemical expression of p16 and p53, molecular markers related to esophageal carcinogenesis in order to verify the potential influence of these variables in patients’s survival. Survival rates were estimated using Kaplan-Meier methods. A multivariate confirmatory model was performed using Cox proportional hazards regression.

Results

Twelve (13.8%) of 87 patients were HPV-DNA positive. Positive reactions of p16 and p53 were 10.7% and 68.6%, respectively. Kaplan-Meier analysis indicated that men (p = 0.025) had poor specific-cancer survival and a shorter progression-free survival (p = 0.050) as compared to women; III or IV clinical stage (p < 0.019) had poor specific-cancer survival and a shorter progression-free survival (p < 0.001) compared to I and II clinical stage; not submitted to surgery (<0.001) and not submitted to chemoradiotherapy (p = 0.039) had a poor specific-cancer survival, as well. The multivariate analysis showed that HPV, p16 and p53 status are not predictive parameters of progression-free and specific-cancer survival.

Conclusion

HPV infection and p53 and p16 expression are not prognostic factors in ESCC.

     

p53 gene mutations and p21 protein expression induced independently of p53, by TGF-β and γ-rays in squamous cell carcinoma cells

p53 gene mutation and the influence of TGF-β and γ-rays on p21 promoter activity, p21 mRNA and protein expression were investigated in nine cell lines (OSC-1 to -9) established from metastatic squamous cell carcinomas (SCC) of the cervical lymph nodes. The direct DNA sequence analysis of exons 2 to 11 of the p53 gene revealed 16 point mutations in all cell lines, but neither deletions nor additions were observed. TGF-β upregulated p21 promoter activity by approximately 2-fold of the control and concurrently increased p21 mRNA expression, except in OSC-8 and -9. However, γ-rays suppressed p21 promoter activity, although p21 mRNA expression in irradiated cells was increased except for OSC-8 and -9. In parallel with the messenger expression, p21 protein expression was strongly increased by TGF-β, but only weakly increased by γ-rays. These results indicate that point mutation of the p53 gene is frequent in metastatic SCC cells and p21 mRNA and its protein expression is p53-independently induced by both TGF-β and γ-rays, although the mechanism of induction by TGF-β and γ-rays is different.     

Lysine-specific modifications of p53: a matter of life and death?

Post-translational modifications provide a fine-tuned control of protein function(s) in the cell. The well-known tumour suppressor p53 is subject to many post-translational modifications, which alter its activity, localization and stability, thus ultimately modulating its response to various forms of genotoxic stress. In this review, we focus on the role of recently discovered lysine-specific modifications of p53, methylation and acetylation in particular, and their effects on p53 activity in damaged cells. We also discuss a possibility of mutual influence of covalent modifications in the p53 and histone proteins located in the vicinity of p53 binding sites in chromatin and propose important ramifications stemming from this hypothesis.     

The role of the unfolded protein response in tumour development: friend or foe?

Having accumulated mutations that overcome cell-cycle and apoptotic checkpoints, the main obstacle to survival faced by a cancer cell is the restricted supply of nutrients and oxygen. These conditions impinge on protein folding in the endoplasmic reticulum and activate a largely cytoprotective signalling pathway called the unfolded protein response. Prolonged activation of this response can, however, terminate in apoptosis. Recent delineation of the components of this response, coupled with several clinical studies, indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.