Jun and Fos are major components of the transcriptional complex AP-1 (Activator Protein-1), a collection of dimeric transcriptional activators composed of members of the Jun and Fos family of bZIP proteins, that bind to a common site known as TRE (TPA Responsive Element) or the AP-1 site. Transcription of c-jun is rapidly induced by exposure to different extra-cellular signals like growth factors, cytokines, tumor promoters (TPA), UV and other DNA-damaging agents. Transcriptional activation of c-jun is a two step mechanism. First, the pre-existing c-Jun protein is activated by posttranscriptional modifications, and second, modified c-Jun activates its own transcription, and the expression of AP-1-dependent genes. Modifications of c-Jun include dephosphorylations, phosphorylations and oxydo-reduction. The transcriptional activation by c-Jun is modulated by heterodimerization with other members of the bZIP family of proteins, and by transcriptional interference with other transcription factors like some members of the hormone nuclear receptors, or MyoD. AP-1 is tightly associated to both the control of cell proliferation and the oncogenic process. Constitutive activation of AP-1 leads to cell transformation in vitro, probably due to the accumulation of homodimeric c-Jun:c-Jun complexes. This hypothesis has been directly confirmed by constructing c-Jun hybrid proteins capable to form only homodimers. Deregulated expression of such proteins efficiently transforms primary cells in culture. These hybrid proteins constitute a powerful tool in order to identify new cellular functions AP-1-dependent, involved in the control of cell proliferation.

The establishment of a cell culture system for the clonal development of hemopoietic cells made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hemopoietic cell lineages and the molecular basis of normal and abnormal development in blood-forming tissues. These regulators include cytokines now called colony stimulating factors (CSFs) and interleukins (ILs). Different cytokines can induce cell viability, multiplication and differentiation, and hemopoiesis is controlled by a network of cytokine interactions. This multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor. The cytokine network which has arisen during evolution allows considerable flexibility depending on which part of the network is activated and the ready amplification of response to a particular stimulus. The CSFs and ILs induce cell viability by inhibiting programmed cell death (apoptosis). Programmed cell death is also regulated by the genes wild-type and mutant p53, c-myc and bcl-2, and suppression or induction of this program can result in tumor promotion or tumor suppression. Cytokines that regulate normal hemopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation. Genetic abnormalities that give rise to malignancy in these leukemic cells can be by-passed and their effects nullified by inducing differentiation and programmed cell death. The hemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in hemopoiesis.

The nm23-H1 gene encoding the nucleoside diphosphate (NDP) kinase A has been proposed as a tumor metastasis suppressor. Two important features emerge from published data: 1) an inverse correlation between the metastatic invasion and the level of NDP kinase/Nm23 was observed in melanomas, hepatocellular carcinomas and, in some studies, on breast carcinomas; 2) an overexpression of NDP kinase/Nm23 was observed in several solid tumors as compared to normal surrounding tissues, positively correlated with aggressiveness in the case of neuroblastomas. The level of NDP kinase/Nm23 in tumors appears to be altered in different ways, related or not to the metastatic potential, depending on the tissue of origin. Its evaluation as a prognostic or diagnostic marker of tumor invasion and aggressiveness deserves further study.

The tumor suppressor genes presently individualized are still few. A step in their identification is the search for chromosomal deletions and loss of heterozygosity. These studies are summarized.

The retinoblastoma is a rare childhood tumor which occurs in children, 40% of them being diagnosed in an hereditary context. The gene involved in the hereditary predisposition and in the tumoral development was isolated (RB-1) and is of the antioncogene-type. RB-1 mutations were found in many other tumors. The absence of the antioncogene protein expression is responsible for the tumor development and a contrario its presence in normal cells has tumor suppressive properties. This property was demonstrated by phenotype reversion of retinoblastoma or other cell lines (with no RB-1 protein), induced by reintroduction of the gene coding for the normal RB-1 protein. The normal RB-1 protein undergoes multiple phosphorylations during the cell cycle, regulating its activity, the active form being hypophosphorylated. RB-1 is involved in the transcription regulation of many cell cycle genes, and in cell differentiation. Experimental animal models are under investigation, in order to established whether RB-1 overexpression in normal cells will protect them from tumor development, and to plan tumor gene therapy by injection of recombinant viruses allowing RB-1 expression in tumor cells.

The p53 gene is known to play a central role in cancer. In fact, no human tumor type is devoid of p53 mutations, although differences can be seen in the relative frequencies and patterns of nucleotide substitutions. Our work illustrates these differences, since frequencies of mutations ranged from 15 to 80% and the patterns of mutations were distinctly different in skin cancers compared to breast tumors. Furthermore, it is well established that whenever p53 mutations occur during tumor progression, their appearance greatly affects the natural evolution of cancer. This is confirmed by the correlations found between p53 mutations and the negative outcome of the disease in a number of tumor types.

The c-Ha-ras-1 polymorphism was studied in 92 bladder tumor samples (newly diagnosed and/or recurrent) obtained from 73 patients and in the paired white blood cells (WBC). A heterozygous state was detected in WBC DNA of 38 patients (52%). The statistical analysis (univariate and multivariate) demonstrated an association between the heterozygous state of the patients and a lymphatic invasion. In patients with a pTa tumor, there was a relation between the heterozygous state and a younger age at diagnosis. A loss of heterozygosity for c-Ha-ras-1 locus was detected in seven out of the 38 informative tumors (18.4%). No significant correlation was observed with the prognostic factors. These results address the relation between the heterozygous genomic state and the risk of lymphatic invasion in the patients with a bladder tumor.

The course of bladder tumours is difficult to predict. The most reliable prognostic factor at the present time is histological grade. Cytogenetic subclasses of bladder tumours can be distinguished on the basis of the demonstration of karyotype anomalies in bladder tumour cells. Eighteen patients underwent cytogenetic examination of their bladder tumour and were followed for an average of 35 months. Multivariate analysis of the clinical and laboratory parameters studied revealed the importance of age and the absence of trisomy 7 in the tumour on patient survival. The presence of trisomy 7 in a bladder tumour may therefore constitute a factor of poor prognosis. This hypothesis needs to be confirmed by further studies in larger populations. The search for this anomaly can be performed by fluorescent in situ chromosomal hybridisation, a technique which transforms cytogenetics from an experimental procedure into a routine complementary investigation. These techniques can be performed on urine samples, suggesting the possibility of their application to screening or follow-up of bladder tumours.

The early diagnosis of digestive cancer is usually based on the detection of the presence epithelial histological abnormalities known as dysplasia. The histological features described constitute an intermediate step between normal tissue and actual cancer. Two degrees of dysplasia are now distinguished: moderate dysplasia and severe dysplasia (the latter being equivalent to in situ cancer or stage 0 cancer). The difficulty in reliably identifying and classifying dysplasia has led to the development of additional methods able to detect abnormalities of the genetic material, particularly of DNA. The use of flow cytometry to examine tissue makes it possible to analyse the DNA content of the tissue nucleus by nucleus. Normal tissues have a normal DNA content and are described as "diploid". Tumor tissues frequently contain abnormal quantities of DNA and are described as "aneuploid". Pre-cancerous aneuploidism could be identified before cancer develops and detected in dysplastic states. The authors report their own experience and that of many other authors of the value of this additional method of investigating precancerous lesions of the digestive tract.