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In Europe, endometrial cancer is the fourth most common cancer among women. The majority of patients are diagnosed at a localized stage. For these patients, the standard of care is based on an hysterectomy with salpingo oophorectomy±lymph node staging. Through the assessment of histopathologic features, risk groups are determined: low, intermediate, high-intermediate, and high risk. Adjuvant strategies are guided by these risk groups. While the prognosis of low-risk and high-risk is well known, that of intermediate and high-intermediate risk is more heterogeneous, and the therapeutic index of adjuvant treatments is more questionable. Several trials (PORTEC [Post Operative Radiation Therapy in Endometrial Carcinoma] I, GOG [Gynecologic Oncology Group] 99, ASTEC [A Study in the Treatment of Endometrial Cancer] EN.5, PORTEC II, Sorbe et al trial) have assessed observation, vaginal cuff brachytherapy and/or pelvic external beam radiotherapy in this population. Vaginal cuff brachytherapy reduces the local recurrence rate, and pelvic external beam radiotherapy the pelvic recurrence rate. However, no benefit in terms of overall survival or occurrence of distant metastases is highlighted. Compared to observation, brachytherapy and above all external beam radiotherapy are associated with an increased morbidity, and with a decreased quality of life. In order to improve the therapeutic ratio and to optimize medico-economic decisions, therapeutic de-escalation strategies, based on the molecular profiles, are emerging in clinical trials, and in the recommendations for the management of intermediate and high-intermediate risk endometrial cancers. The four main molecular profiles highlighted by the genomic analyzes of The Cancer Genome Atlas (TCGA) - POLE (polymerase epsilon) mutation, non-specific molecular profile, MMR (MisMatch repair) deficiency, and p53 mutation - but also the quantification of lymphovascular space invasion (absent, focal or substantial), and the assessment of L1CAM (L1 cell adhesion molecule) overexpression represent growing concerns. Thus, the use of molecular-integrated risk profile to determine the best adjuvant treatment represent a major way to personalize adjuvant treatment of endometrial cancers, with therapeutic de-escalation opportunity for around half of the high-intermediate risks. However, in the absence of prospective data, inclusion in clinical trials assessing molecular profile-based treatment remains the best therapeutic opportunity.

Although some genetic alterations in glioblastoma (GBM) have been characterized, the prognostic value of these gene mutations is not yet established in patients treated with standard therapy.40 patients with newly diagnosed GBM, treated between July 2017 and December 2019, and who had genomic analysis were analyzed. Next-generation sequencing techniques (NGS) were used with a panel of 26 genes. Patients were grouped according to MGMT status, the presence or absence of at least one mutated gene on the panel, and p53 expression by immunohistochemistry.the median follow-up was 11.5 months (1.0-37). For all patients, the median duration of progression-free survival was 8 months (95% CI, 5.3-10.7) and the median overall survival (OS) was 17 months (95% CI, 7.5-26.5). Progression-free and overall survival were significantly different according to MGMT status but not according to NGS and p53 status. Three groups of patients according to different combined status could be distinguished due to significant differences in overall survival.we have shown that the presence of MGMT promoter methylation is a good prognostic factor. By grouping the patients according to their MGMT, NGS and p53 status, three groups of patients could be separated according to their overall survival. However, these results must be confirmed on a larger number of patients.

In this forum, we develop the idea that the human genome may not be equipped to protect us after the age of reproduction against certain diseases such as cancer or neuro-degenerative diseases. We take as example cancer and show that adding one tumor suppressor in the mouse genome in its genomic context (BAC transgene) provides some protection against spontaneous and induced tumors. We also show that in certain species displaying a resistance to cancer, there is an amplification of some tumor suppressor genes.

The nucleolus is a potent disease biomarker and a target in cancer therapy. Ribosome biogenesis is initiated in the nucleolus where most ribosomal (r-) proteins assemble onto precursor rRNAs. Here we systematically investigate how depletion of each of the 80 human r-proteins affects nucleolar structure, pre-rRNA processing, mature rRNA accumulation and p53 steady-state level. We developed an image-processing programme for qualitative and quantitative discrimination of normal from altered nucleolar morphology. Remarkably, we find that uL5 (formerly RPL11) and uL18 (RPL5) are the strongest contributors to nucleolar integrity. Together with the 5S rRNA, they form the late-assembling central protuberance on mature 60S subunits, and act as an Hdm2 trap and p53 stabilizer. Other major contributors to p53 homeostasis are also strictly late-assembling large subunit r-proteins essential to nucleolar structure. The identification of the r-proteins that specifically contribute to maintaining nucleolar structure and p53 steady-state level provides insights into fundamental aspects of cell and cancer biology., SCOPUS: ar.j, info:eu-repo/semantics/published

The p53 gene is essential for tumor suppression, but how it does so remains unclear. Upon genotoxic or oncogenic stresses, increased p53 activity induces transient cell cycle arrest, senescence or apoptosis, the three cornerstones of the so-called triumvirate. Accordingly, it has long been thought that p53 suppresses tumorigenesis by somehow counteracting cell proliferation or survival. However, several recently described genetically modified mice indicate that p53 can suppress tumorigenesis without triggering these three responses. Rather, as an important mechanism for tumor suppression, these mutant mice point to the ability of p53 to prevent the Warburg effect, that is to dampen glycolysis and foster mitochondrial respiration. Interestingly, these metabolic functions of p53 rely, in part, on its "unstressed" (basal) expression, a feature shared by its mechanistically linked anti-oxydant function. Together, these "conservative" activities of p53 may prevent tumor initiation by promoting and maintaining a normal oxidative metabolism and hence underly the "daily" tumor suppression by p53 in most cells. Conversely, destructive activities elicited by high p53 levels and leading to senescence or apoptosis provide a shield against partially or overtly transformed cells. This last situation, although relatively infrequent throughout life, is usual in experimental settings, which could explain the disproportionally high number of data implicating the triumvirate in tumor suppression by p53.

In patients with colorectal cancer, nuclear accumulation of p53 is often associated with poor prognosis and resistance to chemotherapy. Overexpression of HER3 is associated with poor prognosis and resistance to therapy targeting EGFR. Our study was performed on 16 samples of colorectal adenocarcinomas. The pieces fixed in formalin were embedded in paraffin. The study of the expression of p53 and HER3 is performed by immunohistochemical technique. Immunohistochemical study of the expression of p53 showed nuclear accumulation of this protein in 87% of colorectal adenocarcinomas analyzed. Regarding the HER3 receptor overexpression was observed in 56% of cases. Overall, 50% of the cases co-expressed p53 and HER3. HER3 and p53 are important markers of colorectal cancer because they provide information about the distinctive biological characteristics of tumors. The prognostic and predictive value of the combination of these two markers could be an important clinical tool.

Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact.

Two major pathways are described in bladder carcinogenesis: one for invasive or high grade tumors characterized by alteration of the p53 tumor suppressor gene and the other for non-invasive tumors or low grade involving mutations FGFR3. The objective of our study was to validate the research in the urine of mutations in these two genes in patients with a bladder tumor.In our preliminary study, we investigated 36 patients the FGFR3 and p53 mutations in tumors and urine collected during endoscopic resection. The p53 mutations were sought in FASAY, which allows a functional analysis of the protein P53. The FGFR3 mutations were sought in SNaPshot that searches the eight most frequent mutation points of this gene.For 24 patients (66% of cases), we found at least one of the two mutations in the tumor. This mutation was present in the urine in 15 patients (sensitivity=62.5%). In only one patient, we found a mutation in the urinary sediment that did not exist in the tumor (specificity=91.7%).The search for mutations of p53 and FGFR3 in the urine was a simple and non-invasive assay, which seems superior to urinary cytology for the detection of bladder tumors, raising hopes of an interest in this bio-assay for surveillance of bladder tumors and screening risk populations.

Cellular senescence is, essentially, a permanent proliferation arrest induced by various cellular stresses or inappropriate stimuli. This arrest, which is associated with dramatic changes in cell morphology, metabolism and gene expression, involves a complex signalling network aiming at stable inactivation of CDKs, major cell cycle regulators. Notably, several tumour suppressors, such as p53, pRb or p16(Ink4a), play key roles both in the initiation of the senescence program and in its maintenance, which often involves epigenetic changes. While having widely recognized roles in tumour suppression and wound healing, senescence, like the roman god Janus, recently revealed another darker face. Mostly due to altered secretion phenotype favouring inflammation, senescent cells strongly influence surrounding tissue contributing to the development of age-related pathologies, including cancer.

The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities.

P53 is 30. Even if the tumor suppressor functions of p53 have long been recognized, the cancer-killing activity of p53 has not yet been exploited selectively and efficiently in the clinic. Recent genetic studies in mice identified MDM2 and MDMX as key regulators of p53 and as such as specific chemotherapeutic targets for treatment of cancer. Specific MDM2 and MDMX antagonists are now being developed as tools to unleash p53 activity in various tumors.

Nasopharyngeal carcinoma (NPC) is an unusual head and neck cancer because of its unequal geographical distribution and its consistent association with the Epstein-Barr virus (EBV). This malignant tumor poses a serious public health problem in many countries, especially in Southeast Asia and North Africa where the recorded incidence are highest. During the past decade, a growing number of studies were undertaken to define the molecular basis of NPC. However, the analysis of several clinical and biological parameters of North African and Southeast Asian NPCs has shown notable differences, suggesting that they could result from a distinct combination of etiological factors. One intriguing characteristic of North African NPC, concerns its bimodal age distribution with a secondary peak of incidence in the range of 15-25 years, not observed in Asian NPC. In this juvenile form of NPC, immuno-histochemistry assay has shown that the two key proteins controlling the apoptotic-survival balance p53 and Bcl-2 are less frequently expressed whereas the transmembrane tyrosine-kinase receptor c-kit and the main EBV oncoprotein LMP1 were more abundant. In addition, the EBV serological alterations are less informative for the diagnosis of the juvenile compared to the adult form. In addition, most North African NPCs contain EBV strains with genetic polymorphisms distinct from those described in the Southeast Asia series (predominance of F, D, H1-H2, XhoI+ and f, C, H, XhoI- respectively). In contrast, studies relating on tumor chromosomal alterations or aberrant promoter methylation result in data very similar to those obtained from the Southeast Asia series, supporting the concept of a common molecular basis for all NPC regardless of patient geographic origin.

The risk to develop melanoma from small or medium size congenital naevus remain controversial. The main goal of the present study was to determine the interest of three immunohistochemical markers (Ki67, HMB45 and p53) in predicting malignant transformation of these congenital naevi and to see if a specific immunohistochemical profile of such transformed naevi can be identified. The markers (Ki67, HMB45 and p53) have been used retrospectively on sections of small or medium size congenital naevi (group NC, n = 15), of melanoma developed on small or medium size congenital naevi (group MNC, n = 15) and of melanoma developed on acquired naevi (group MNA, n = 15). The labelled cells have been counted in different cutaneous layers: junction, superficial dermal layer and deep dermal layer. No reactivity was observed for the three markers in group NC. The percentage of labelled cells was significantly different for the three markers between the group NC and the groups MNC and MNA. There was no difference between the groups MNC and MNA. In the groups MNC and MNA, a gradient in the percentage of labelled cells was observed between superficial and deep layers. These three markers do not differentiate melanoma developed from congenital naevi of small or medium size and melanoma developed from acquired naevi. Moreover, the results suggest that these three markers are useless in predicting the risk of malignant transformation of small or medium size congenital naevi.

Human papillomavirus (HPV) is one of the most common causes of sexually transmitted infection in the world. France and Belgium present one of the highest incidence of head and neck squamous cell carcinomas (HNSCC) worldwide. Besides, considering only the male population, HNSCCs represent the fourth most frequent cancer after prostate, lung and colon cancers. Although the causal link between high-risk HPVs and cervical carcinoma is well established, the implication of this viral infection in HNSCC remains debatable. Here, we discuss current knowledge concerning the HPV implication in HNSCCs. Based on our literature review, 20 to 25% of HNSCCs could be associated with oncogenic HPVs, in particular HPV type 16. The oropharynx--more precisely the tonsil--is the head and neck location presenting the highest incidence of HPV infection. Moreover, a clear increase of tonsillar carcinoma incidence has been described. As observed in cervical carcinomas, HPV positive HNSCCs are sexually transmitted and characterized by alterations of p53 and pRb signalling pathways. Several studies have shown that HPV positive subgroup presented better prognosis particularly if these patients overexpressed p16INK4. New studies regarding HPV status in HNSCCs are warranted to provide a rationale for large scale HPV vaccination in young male populations.

Most adrenocortical tumors are benign; adrenocortical carcinomas are rare but their prognosis is poor and their therapeutic is sparse. In most adrenocortical tumors, the morphological approach brings sufficient elements to establish the differential diagnosis between a benign and a malignant tumor but in few cases, it is insufficient. Moreover, morphology is limited for predicting prognosis of adrenocortical carcinomas. These observations led to development of other approaches, in particular genetic approaches. These genetics findings already have repercussions for the patients in the development of molecular markers for diagnosis and prognosis and in the future they could help in the development of new morphological approaches, in particular immunohistochemical approaches.

Considering both the clinical and molecular heterogeneity of breast cancers, one can easily conceive that all tumours are not equally sensitive to the different chemotherapy agents or regimens used. Thus, the identification of predictive markers of chemosensitivity should be considered as a research priority and we analyse here this question in two parts: (1) identification of predictive markers of general chemosensitivity, which means that a tumour is sensitive to any chemotherapy; (2) identification of predictive markers of specific chemotherapy which means that a tumour is sensitive to a specific cytostatic class or to a specific regimen. We will address these two aspects and will summarise ongoing trials and recently published data. These studies suggest the predictive value of biological markers either considered as single molecular markers (hormone receptors, HER2, TOPO2alpha, p53) or as multiple markers combined in so-called "signatures".

Nodular fasciitis rarely affects children. To date, apart from isolated cases, only two series comprising respectively 15 and six children have been reported.We carried out a retrospective study of the clinical and pathological aspects of 10 cases of nodular fasciitis involving children under 15 years of age diagnosed at the pathology laboratory of the Necker Children's Hospital (Paris, France) between 1992 and 2006.In comparison with previously reported data, our study highlights four new factors: (1) nodular fasciitis affected girls more often than boys; (2) it occurred predominantly on the trunk; (3) follow-up showed a high recurrence rate (22%) after surgical removal; (4) immunohistochemical analysis revealed a high level of expression of p53 by tumour cells; this was much higher than in adults.The high expression of p53 in nodular fasciitis, which has never been described in children, seems to point towards its preneoplastic rather than reactive nature.

Many predictive factors of tumor radiosensitivity have been described. Number of clonogenic cells, proliferation rate, hypoxia and intrinsic radiosensitivity are usually considered as the main parameters of tumor control. Intrinsic radiosensitivity is correlated in a first approach to the ability of the cell to detect and repair DNA damages, and so integrity of the different pathways involved in this function: PARP-1, XRCC1, ATM, p53, MRN complex or BRCA1... Genetic polymorphisms of some of these genes, found in normal lymphocytes, have been correlated to late toxicity of normal tissues. But, in tumors, because of the difficulty to obtain samplings and heterogeneity, accurate molecular analysis is not possible in many cases, and no valuable test of radiosensitivity exist at this moment. For example, TP53 gene has been evaluated in many studies and results regarding its potential as a predictive factor of tumor sensitivity are conflicting. Surviving fraction at 2Gy (SF2) allowed a global evaluation of sensitivity, but the obtention of this parameter often takes a long time and failed in 20 to 40%. Evaluation of double-strand break repair capacity by immunochemistry quantification of phosphorylated forms of ATM, H2AX or MRE11 is an interesting topic. However, discovery of tumor stem cells in a number of epithelial tumors could revolutionize the understanding of radiosensitivity. Combination of genomic and functional techniques are probably essential to better predict this parameter.

International audience; The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic alterations and molecular expression in experimental models as well as in pre-cancerous and cancerous tissues by mean of molecular amplification and large scale transcriptome analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis and detecting its mutation in tumor samples could have a clinical relevance in term of positive (improvement of current histological diagnosis) and differential diagnosis (versus chronic pancreatitis) of pancreatic cancer. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, nerve growth factor, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, beta integrin, urokinase and tissue plasminogen activator) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. New markers and targets are currently studied among microRNA and epigenetics events such as methylation and acetylation. Among all these molecular markers, some are now tested for their potential clinical interest in term of diagnosis or therapeutic target.

To study a serie of superficial tumors of the bladder and to assess the prognostic significance of p53, Ki67, PCNA and bcl2 in these tumors.We studied 59 bladder tumors: 43 pTa and 16 pT1. All Patients had cystoscopy 3 months after the resection and tumors that did not recur had a minimum follow up of 5 years.Age more than 65 years (p = 0,001), multifocality (p=0,022) and tumoral sizeor = 3 cm (p = 0,022) were correlated with the recurrence. The expression of p53 was correlated with the recurrence in the year following the tumoral resection (p = 0,035). That of of Ki67 was correlated with the histological grade (p = 0,03) and stage (p=0,002).Our results suggest to practise regular endoscopic controls during the first year following the resection of the primitive tumor if it expresses p53. The immunohistochemical expression of Ki67 being correlated with the grade, this marker could help to better classify the tumors of intermediate grade.

International audience; Protein-protein interactions have a key role in transduction pathways that regulate many cellular functions. Structural and functional properties of protein-protein interface are now better understood, therefore offering attractive opportunities for therapeutic intervention. Developping small molecules that modulate protein-protein interactions is challenging. Nethertheless, significant progress in this endeavour has been made on several fronts. Here, we use few illustrative examples to summarize recent work in this emerging field.

Germ cells perform a unique and critical biological function: they propagate the DNA that will be used to direct development of the next generation. Genetic integrity of germ cell DNA is essential for producing healthy and reproductively fit offspring. There is accumulating evidence that genetic damage, in the form of unrepaired DNA lesions or de novo mutations, may be transmitted via sperm to offspring. Such genetic damage may arise from environmental exposure or via endogenously formed reactive species, in stem cells or during spermatogenesis. Based on results from our own and other laboratories, we discuss the current knowledge of different pathways of DNA repair, especially in human oocyte.

Mucoepidermoid carcinoma is one of the most frequent malignant lesions of salivary glands. The treatment is based on clinical, paraclinical and histological data. Several studies on the prognostic value of molecular markers for these cancers were made with contradictory results. The aim of this retrospective study was to analyze the prognostic value of molecular markers of salivary gland mucoepidermoid carcinoma.Sixteen patients were treated for mucoepidermoid carcinoma of principal and/or accessory salivary glands between 1994 and 2003. An immunohistochemical study of archive specimen was performed. Nine markers were specifically studied: 4 proteins/oncoproteins (p53, bcl2, c-erb-B2 and cd117), 2 markers of proliferation (PCNA and Ki67), 1 growing factor receptor (EGFR), 1 epithelial adhesion molecule (E-cadherin), and 1 angiogenic cytokine (PDGF).Nine men and 7 women were included, with a mean age of 43.7 years (14-80). The mean diameter of tumors was 3.1 mm (1-14), and the parotid gland was the most frequent location. The mean global survival rate was 57.3 months with a median of 55 months. The 2 to 5 years survival expectation rate were 82.5% and 46.4% respectively. The mean survival rate for women was superior to that of men (P=0.043). The expression of p53 and the high expression rate of EFGR were bad prognostic factors (respectively P=0.049 and P=0.012). The expression of PCNA was linked to the location (mainly the salivary gland) and to the diameter of the tumor (respectively P=0.037 and P=0.029). The degree of EFGR positivity and the histological grade were linked (P=0.027).The strong expression of EGFR was statistically linked to the histological tumor grade. The degree of PCNA positivity seemed to be associated to the preferential location in the main salivary glands and to the diameter of the tumor. The strong expression of p53 and EGFR were bad prognostic factors. These retrospective results need to be confirmed by prospective randomized and larger studies. EGFR and p53 were significant negative prognostic factors. EGFR was highly correlated to the histological grade, making it an interesting target for further investigation.

Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy.

A major obstacle to the expansion of abnormal cells with significant proliferative potential is the induction of either cellular senescence or programmed cell death. Consequently, oncogene-driven hyperproliferation must be associated with apoptosis inhibition to allow malignant outgrowth. The oncogenic cooperation of N-Myc and Twist 1 in the development of neuroblastoma, the most common and deadly solid tumour of childhood, perfectly illustrates such a process. N-Myc promotes cell proliferation whereas Twist 1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway. This observation provides a mechanistic explanation for the rarity of p53 mutations in neuroblastomas. It also highlights the involvement of two crucial regulators of embryogenesis in human cancer development. In this review, we discuss the possible role of Twist 1 in tumour progression, based on the numerous recent studies reporting its overexpression in a variety of human cancers.

Proteasome-mediated proteolysis is a mechanism for mediating important regulatory proteins within the cell. Proteins that have been targeted for degradation by the proteasome are convalently tagged with a poly-ubiquitin protein chain prior to be recognized by the 19S subunit of proteasome. This degradation system controls the expression of a wide variety of cellular targets including tumor suppressors such as p53, inhibitor of nuclear factor NFkappaB, cyclin-dependent kinase inhibitors such as p21 and p27. Because of these functions, the proteasome has become a new target for cancer treatment. The potent and selective proteasome inhibitor, PS-341 or Velcade was approved in the United States and launched in may 2003 for the treatment of multiple myeloma patients who have received at least two prior therapies. On April 2004, the European commission granted marketing authorization for Velcade with the same indication. The same year 2004, the Nobel Prize in chemistry was awarded to three researchers "for the discovery of ubitiquin-mediated protein degradation", a regulated process by which proteins are cleaved into peptides inside cells.

Loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p) is one of the most frequent genetic alterations in human cancers. Most often, allelic losses coincide with p53 mutations at 17p13.1. However, in many types of solid tumors including sporadic breast cancers, ovarian cancers, medulloblastomas and small cell lung carcinomas, frequent LOH or DNA methylation changes occur in a more telomeric region at 17p13.3, in absence of any p53 genetic alterations. These results suggest that one or more tumor suppressor genes located at 17p13.3 could be involved in tumorigenesis. In addition, the 17p13.3 region has also been implicated in the Miller-Dieker syndrome (MDS), a severe form of lissencephaly accompanied by developmental anomalies caused by heterozygous gene deletions. Analyses of deletion mapping and CpG island methylation patterns have resulted in the identification of two tumor suppressor genes at 17p13.3, HIC1 (hypermethylated in cancer 1) and OVCA1 (ovarian cancer gene 1). HIC1 is a tumor suppressor gene that encodes a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and a N-terminal BTB/POZ domain. Clues to the tumor suppressor function of HIC1 have come from the study of heterozygous Hic1+/- mice, which develop spontaneous malignant tumors of different types. Generation of double heterozygous knockout mice Hic1+/- p53+/- provides strong evidence that epigenetically silenced genes such as HIC1 can significantly influence tumorigenesis driven by mutations of classic tumor suppressor genes. This functional cooperation between HIC1 and p53 is interesting and recently, its has been demonstrated that HIC1 was involved in a certain feedback regulation for p53 in tumor suppression through the histone deacetylase SIRT1. However, despite the fact that epigenetic oncogenesis is one of the most vibrant areas of biologic research, the determinants between genetic versus epigenetic routes of tumor suppressor gene inactivation remain elusive.

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the presbyacusis in the population. The biological and molecular causes of this degenerative pathology of the inner ear are linked to the disappearance of the sensory cells (inner and outer hair cells) and are associated to nervous damages of the spiral ganglion in the cochlea. We were interested in mechanisms causing the cochlear degeneration in a model of mouse CD 1 presenting prematurely auditive losses.We tried to correlate the evolution of the hearing and the appearance of apoptotic phenomena by marking with specific antibody, activated anti-caspase-3, in the cochlea during time. We studied the role and the involvement of proteins controlling the apoptosis as the P53 protein and from an energy point of view at the level of the mitochondria such as proteins of the Bcl-2 family and the cytochrome c in the various structures of the cochlea.After implantation of electrodes for auditory nerve acoustic thresholds measurements, the audition of mice CD 1 presented a characteristic profile of hearing losses which begins in the high frequencies from the age of 1 month and which quickly evolves towards the low frequencies. The observation (between the 1st and 3rd month of age) of spiral ganglion cells revealed an unchanged number of cellular bodies of type 1 neurons, on the other hand a characteristic morphology of apoptosis of glial cells with the formation of apoptotic body was noted. Indeed, glial cells expressed activated caspase-3. Furthermore, this phenomenon seems to be under the control of the pro-apoptotic protein Bax by its overexpression and a increased release of the cytochrome c. This phenomenon was followed at 3 and 6 months by the disappearance of the outer hair cells by 9 and 48% respectively.The apparition of the deafness in the murin model CD 1 allowed us to demonstrate that the degeneration of cochlear structure begins at the level of glial cells of the spiral ganglion from 3 months, followed thereafter by the deterioration of the nervous conduction between the spiral ganglion and the sensory cells. As a consequence, because of the impoverishment in nervous signals, the outer hair cells would begin to disappear during the 6th month. In conclusion, the understanding of the sequence and the cause of these mechanisms responsible for the neural degeneration and the loss of hearing could eventually, allow us to optimize the various treatments of the presbyacusis.

The neural crest-derived mesectoderm gives rise to physiologic apoptosis areas in early vertebrate embryos. Certain teratologic agents increase this phenomenon. The purpose of this work was to detect caspase 3 (which is associated with the apoptosis cascade) and p53 in cell death areas, both during physiological apoptosis and during apoptosis induced by three agents (retinoic acid, methyl-triazene, irradiation). Antibody revelation was performed using the aBC peroxidase kit. Quantifications were also performed on histological sections. We observed caspase 3 uptake on some apoptotic and preapoptotic cells in control embryos, and in the embryos exposed to the three teratogens. Immunoreactivity generally preceded the development of cytological features of apoptosis. However, p53 was expressed only in the embryos exposed to ionizing radiation and methyl-triazene (an alkylating agent), but not significantly in embryos exposed to retinoic acid. The present results throw some light on apoptosis mechanisms in several teratologic conditions.

Biliary papillomatosis is a papillary adenomatosis of the biliary mucosa of the extra- and the intrahepatic biliary tree. It is a rare neoplasm difficult to manage, characterized by extensive lesions and a great potential for malignant transformation. We report a case of a 75 year-old man, who presented with malignant papillomatosis of the common bile duct without involvement of the intrahepatic biliary ducts. Duodenopancreatectomy enabled the diagnosis of papillomatosis lined 5.5 cm of the common bile duct which displayed an invasive 1.5 cm papillary carcinoma located in the distal portion of the choledocus. Immunohistochemistry showed strong expression of p53 in the distally located invasive carcinoma and in distant dysplastic lesions. MUC5AC was exclusively detected in both malignant and dysplastic lesions without detection of MUC1 or MUC2. Detection of p53 expression on biliary brush samples could be interesting for the follow-up and the prediction of malignant progression in multifocal biliary papillomatosis.

During the two least decades, the field of tumor immunology has met an expansion of knowledge about the molecular and cellular bases of immune regulation. The identification of cancer antigens has been of critical importance and cancer vaccine is at present a very fast moving field. However, the immunotherapy approaches in cancer are of modest success. This is mainly due to the capacity of tumor cells to escape from immunological detection and to resist to cell mediated cytotoxicity. We will discuss some mechanisms associated with the acquisition of this tumor resistance and the alteration of T cell function and how cancer profiling through genomics approaches may help to reconceptualize immunotherapy strategies.

Integrins are a family of heterodimeric transmembrane receptors that mediate cell-cell and cell-extracellular matrix adhesion. Integrin-mediated signaling is essential for the regulation of fundamental cellular functions, including proliferation and survival, and for tumor development. According to in vitro studies, integrin ligation by extracellular matrix proteins can modulate the cytotoxicity of anti-tumor agents, in a cell-type sensitive manner. Underlying molecular mechanisms are not well understood, but may be based on the interrelations between integrin signaling pathways and pathways that control cell cycle and apoptosis. On the other hand, alterations of integrin expression and/or function have been observed during the acquisition of chemoresistance in cells chronically exposed to cytotoxic agents. These data are in favor of a role of integrins in chemoresistance processes, and open new perspectives in the field of cancer therapy and prognosis.

A 41-year-old female presented in April 1996 with a tumor of the hard palate revealed by increasing left palate pain. Adenoid cystic carcinoma was suspected on clinical and imaging data. Two limited surgical procedures showed a tumor histologically made of small lobules of granular cells, PAS positive and expressing S100 protein, infiltrating some medullary spaces of the palatine bone, consistent with a granular-cell tumour. Pain recurred in the territory of the maxillary branch of the left trigeminal nerve (V2). Imaging showed a tumor of the origin of V2-extending through the foramen rotondum. Two radical interventions in September and in October 2000 showed an infiltrating tumor of the V2 and palatine mucosa, with the same histology. There was no immuno-staining for p53, and less than 5% of nuclei expressed Ki67. Malignant Abrikossof tumors are exceptional, morphologically difficult to differentiate from benign ones, only metastasis proving malignancy. Tumor size above 5 cm, recurrence and infiltrative character are considered pejorative. The value of p53 and Ki67 expression remains controversial. We discuss our observation according to these criteria.

A general overview of the activation mechanisms of programmed cell death or apoptosis following an irradiation is given in this review. First, are summarized the main induction pathways of radiation-induced apoptosis by which extracellular (tumor necrosis factor (TNF), Fas ligand, TNF-related apoptosis-inducing ligand (TRAIL)) and intracellular (mitochondria and caspases) signals are integrated. A second part is then devoted to the importance of p53 and of its regulators (ATR, ATM, DNA-PKcs) in the process of radiation-induced apoptosis. Thereafter, signal transduction pathways and more specially the role of some protein kinases (MEKK, SAPK/JNK, p38-MAPK) is treated. At last, a chapter concerns the clinical interest of radiation-induced apoptosis and the implication of apoptosis in the treatment of certain diseases.

In the past decade, numerous mechanisms of resistance have been described, involving the availability of the drug at the target or the availability of the target itself, but resistance to cell death induction remains far from being understood. The involvement of p53, of Bcl2 and related proteins, of the Fas/Fas-L system and other membrane death receptor pathways, have especially been studied. However, conflicting results have been published concerning the impairment of apoptosis in resistance to cytotoxic drugs. This has shed important doubts on the currently accepted view, which presents apoptosis as a universal determinant of drug activity. These discrepancies are likely to be related to the cell-type specificity of apoptotic pathways and further research is warranted to get a complete picture of the role of cell death inhibition as a drug resistance mechanism. New genetic tools have been recently made available for the study of anticancer drug resistance. Differential or subtractive analyses of gene expression in drug-sensitive and drug-resistant cell lines or tumors have allowed the identification of genes which are potentially responsible for drug resistance, and which had not been recognized previously by the usual analytic approaches. The generation of genetic suppressor elements represents a more functional approach since they can be selected upon the actual resistance properties of the cell lines. Global transcriptome analysis can be performed through the use of cDNA microarrays, either for the comparison of drug-sensitive and resistant cell lines, or for the study of drug effects on gene expression. This may allow the identification of drug-response genes (whose expression is altered by the drug) and of signaling and metabolic pathways involved in drug activity.

Replicative senescence is defined for human diploid fibroblasts in culture as a cell growth arrest appearing beyond 50 +/- 10 population doublings and associated with telomeres' shortening. This phenomenon shows an increased expression of growth cell inhibitors: p21Waf1 described as an universal CDK inhibitor and p16INK4a as a specific inhibitor for both G1 phase kinases CDK4 and CDK6. The cell proliferation inhibitor p14ARF, product of INK4a/ARF locus is involved in replicative senescence too. Overexpression or homozygotic deletion of these inhibitors demonstrated their role in senescence induction. These proteins are involved in two different metabolic pathways, the first including p53, represented by E2F, ARF, MDM2, p53, p21Waf1, and the second concerning pRb and p16INK4a. These two pathways present numerous interactions and the polymerase (PARP) in relation with p53 and activated by telomere shortening might represent via p21Waf1 a link between this shortening and cell cycle control. An another metabolic pathway involving PTEN and p27KIP1 is discussed in senescent-like phenotype induction, but its activity in replicative senescent is uncertain.

The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.

The antioncogene p53 has been the subject of many studies in the field of bladder cancer, for many years and there appears to be a good correlation between p53 protein overexpression and pejorative clinicopathological factors, but contradictory results have been reported concerning its prognostic value. These discordances can be partly explained by the various immunohistochemical methods used in published series. Standardization of a highly sensitive and specific immunohistochemical method for the detection of p53 alterations now appears to be essential in order to accurately determine the value of p53 in the clinical management of bladder cancer.

Comprehension of cell cycle regulation mechanisms has progressed very quickly these past few years and regulators of the cell cycle have gained widespread importance in cancer. This review first summarizes major advances in the understanding of the control of cell cycle mechanisms. Examples of how this control is altered in tumoral cells are then described.The typical mammalian cell cycle consists of four distinct phases occurring in a well-defined order, each of which should be completed successfully before the next begins. Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of a family of serine-threonine protein kinases, the cyclin dependent kinases (CDK). The timing of their activation is determined by their post-translational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory subunit of the kinase complex. The cyclin family is divided into two main classes. The 'G1 cyclins' include cyclins C, D1-3, and E, and their accumulation is rate-limiting for progression from the G1 to S phase. The 'mitotic or G2 cyclins', which include cyclin A and cyclin B, are involved in the control of G2/M transition and mitosis. The cyclins bind to and activate the CDK, which leads to phosphorylation (and then inhibition) of the tumor suppressor protein, pRb. pRb controls commitment to progress from the G1 to S phase, at least in part by repressing the activity of the E2F transcription factors known to promote cell proliferation. Both the D-type cyclins and their partner kinases CDK4/6 have proto-oncogenic properties, and their activity is carefully regulated at multiple levels including negative control by two families of CDK inhibitors. While members of the INK4 family (p16INK4A, p15INK4B, p18INK4C, p19INK4D) interact specifically with CDK4 and CDK6, the CIP/KIP inhibitors p21CIP1/WAF1, p27KIP1 and p57KIP2 inhibit a broader spectrum of CDK. The interplay between p16INK4A, cyclin D/CDK, and pRb/E2F together constitute a functional unit collectively known as the 'pRb pathway'. Each of the major components of this mechanism may become deregulated in cancer, and accumulating evidence points to the 'pRb pathway' as a candidate obligatory target in multistep oncogenesis of possibly all human tumor types.Major advances in the understanding of cell cycle regulation mechanisms provided a better knowledge of the molecular interactions involved in human cancer. This progress has led to the promotion of new therapeutic agents presently in clinical trials or under development. Moreover, the components of the cell cycle are probably involved in other non-cancerous diseases and their role must be defined.