Roger Monier

The causes of cancer in France

BACKGROUND While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce. METHODS We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985. RESULTS In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers. CONCLUSIONS While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

An estimate of cancers attributable to occupational exposures in France.

Objective: To perform a quantitative estimate of the proportion of cancers attributable to occupational exposures in France in 2000. Methods: Exposure data for established carcinogens were obtained from a 1994 survey and other sources. Relative risks for 23 exposure-cancer combinations were derived from meta-analyses and pooled analyses. Results: A total of 4335 cases of cancer among men (2.7% of all cancers) and 403 cases among women (0.3% of all cancers) were attributed to occupational exposures. Asbestos, polycyclic aromatic hydrocarbons, and chromium VI were the main occupational carcinogens in men, and asbestos and involuntary smoking were the main carcinogens in women. Corresponding proportions for cancer deaths were 4.0% and 0.6% in men and women, respectively. Lung cancer represented 75% of deaths attributable to occupational exposures. Conclusion: Our estimates are comparable with those obtained for other countries in studies based on similar methodology.

Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells

An abnormal stimulation of the cAMP pathway has been recognized as the primary event in various pathological situations that lead to goitrogenesis or thyroid tumors. Thyroid adenomas are monoclonal neoplasms that become independent of thyroid stimulating hormone (TSH) in their secretory function and growth. Mutated forms of the TSH receptor (TSHR) and the adenylyl cyclase-activating Gsα protein, which confer a constitutive activity on these proteins, have been observed in human adenomas. The FRTL-5 rat thyroid cell line is a permanent but untransformed line; the growth of which depends on the presence of TSH, and at least in part, on the stimulation of the cAMP pathway. In order to compare the oncogenic potential of the activated mutant Gsα protein and the constitutively activated TSHR, we have transfected FRTL-5 cells with an expression vector bearing either the cDNA of the Gsα gene carrying the A201S mutation or the cDNA of the TSH receptor carrying the M453T mutation recently identified in a case of congenital hyperthyroidism. The expression of these two cDNAs was driven by the bovine thyroglobulin gene promoter. We show that, although the expression of both the Gsα or TSHR mutant proteins leads to TSH-independent proliferation and to constitutive cAMP accumulation in FRTL-5 cells, only the mutant TSHR is able to induce neoplastic transformation, as demonstrated by growth in semi-solid medium and tumorigenesis in nude mice.

Cancérogenèse. Accroissement des connaissances et évolution des concepts

The understanding of carcinogenesis has greatly increased during the past two decades. The monoclonal origin of most human cancer has been confirmed as well as the multi-step process, which leads to an invasive cancer. However, the process appears to be far more complex than previously suspected. There are numerous and powerful defense mechanisms, which explain why invasive cancers are relatively rare, despite the huge number of actively proliferating stem cells and progenitors, which are exposed to mutagens and could be transformed. During the carcinogenic process these defenses have to be overcome or circumvented. The reactive oxygen species (ROS) produced in cells during oxygen metabolism are potent mutagens. Their formation is increased during oxidative stress. At the cell level, defense mechanisms include: anti-oxidant mechanisms, which destroy or scavenge ROS and are activated following an oxidative stress. The defense mechanisms also include DNA repair and elimination by death (mainly apoptosis) or senescence, of the cell with an altered or dysfunctional genome. At the tissue and micro-environment levels several mechanisms preserve tissue structure. They also kill aberrant cells or block their proliferation by means of the release of various cytokines. Moreover, immunosurveillance systems fight against the preneoplastic cells, which are considered by them as foreign cells. Conversely, promoters are agents, which stimulate the proliferation of initiated cells and/or perturb intercellular communication, reducing by this means the constraints exerted by normal cells on aberrant cells. Inflammation and infection have a promoting effect. During promotion, the preneoplastic-transformed cells become more autonomous and can acquire the ability to manipulate protective mechanisms. This phase ends when some cells are fully automonous and proliferate even when promoting agents are lacking. During the next phase, that of progression, the transformed cell becomes able to invade surrounding normal tissues and eventually to migrate. Contrarily to what was believed two decades ago, statistical calculations have shown that accumulation of such a large number of specific genomic damage cannot be due to chance. Initiation can be a stochastic process but carcinogenesis cannot be. This accumulation of several specific changes is facilitated when, due to an apoptosis defect, cells with somatic mutation are not eliminated. This defect opens the way to clonal amplification of aberrant cells. Intense cell proliferation or genetic instability also increases the propensity to accumulate genetic damage. The fully transformed cells can acquire the ability to escape the control mechanisms, which preserve tissue structure, but this escape can also be due to tissue disorganization such as that caused by the death of a large number of cells (following, for instance, exposure to a large dose of a genotoxic agent) or impairment of cell interaction or to a disease, which causes tissue disorganization (such as cirrhosis of the liver or lung fibrosis). Cancer is not simply caused by the transformation of one cell, which has become autonomous; it is also, and possibly mainly, the consequence of the inability of the tissue and the micro-environment to inhibit the proliferation of this cell or to eliminate it. The delay between the exposure to a carcinogenic agent and the clinical emergence of cancer is due to two factors: the duration of the carcinogenic process and the growth of the tumor (the tumor growth from one cell to 109 cells, a tumor of one gram, corresponds to 30 doubling times; for a tumor doubling time of 3.5 months, which is a common value, this corresponds to approximately 9 years). The carcinogenic effect of low-doses of a carcinogenic agent (tobacco, alcohol, genotoxic agents) has long been debated. Its assessment cannot be based only on epidemiology because even if no cancer excess is evidenced small excess cannot be excluded. Usually, this possible excess is estimated by the extrapolation to low-doses of the dose-effect relationship observed at moderate or high exposure. A linear relationship without a threshold (LNT) is often used for this purpose. Epidemiological data show that promoter agents (hormones, alcohol) are more frequently involved than genotoxic agents in the induction of human cancers. For these, the use of LNT has no scientific rationale. The LNT assumes a cancer risk, which is constant (per dose unit) irrespective of the dose and the dose rate. In fact for tobacco, the epidemiological data show that the cancer risk is not proportional to the dose that is to the number of cigarettes smoked per day; it is proportional to the square of their number (Doll and Peto 1981). For cancer of the oesophagus, the logarithm of the cancer risk is proportional to the amount of alcohol ingested per day, which means that the risk (per dose unit of alcohol) increases very abruptly with the daily dose. For genotoxic agents such as UV or ionizing radiation, the rationale for the use of LNT was that the damage caused to DNA is proportional to the dose. In view of the paramount role of cell defenses and their greater efficiency at low-dose and dose-rate than at high and therefore the lower carcinogenic effect (per unit dose) following low-doses, the use of LNT for genotoxic agents is open to question. These examples show the great importance of fundamental biological research for the assessment of cancer risk, in particular, but not only, for low-doses. Development of both epidemiological and biological research is required in order to prioritize the measures that have to be taken in cancer prevention.RésuméDepuis deux décennies, les connaissances sur la cancérogenèse ont grandement progressé. L’origine monoclonale des tumeurs humaines et leur évolution en plusieurs étapes (initiation, promotion, progression) n’ont pas été remises en question, mais l’ensemble du processus apparaît beaucoup plus complexe qu’on ne le pensait. En particulier, l’existence de mécanismes de défense puissants et multiples explique la relative rareté des cancers malgré le nombre gigantesque de cellules susceptibles de se cancériser et dont l’ADN peut être altéré au cours de la division cellulaire (synthèse de l’ADN et mitose), ou sous l’effet de génotoxiques, notamment les radicaux oxydants nés au cours du métabolisme de l’oxygène. Au niveau des cellules, on distingue trois mécanismes de défense: 1) l’apparition après un stress oxydatif de systèmes anti-oxydants; 2) l’élimination des cellules dont le génome a été lésé soit par la mort (notamment l’apoptose), soit par la perte de la capacité de se diviser (sénescence); 3) les différents systèmes de réparation réparent l’ADN de façon généralement fidèle, mais parfois (surtout quand le nombre de lésions est élevé) en introduisant des erreurs (mutation). Le chapitre 1 est consacré aux modifications génétiques et épigénétiques provoquées par les cancérogènes et au classement de ceux-ci. Le chapitre 2 décrit le processus de cancérogenèse tel qu’il a été établi par les études expérimentales et les observations cliniques, avec ses trois étapes (initiation, promotion, progression). Le chapitre 3 concerne les événements biochimiques au cours de la cancérogenèse et le chapitre 4 les mécanismes de défense des cellules, des tissus et de l’organisme contre la cancérisation. Ceux-ci étaient totalement ignorés, il y a 25 ans, et constituent aujourd’hui un des aspects les plus fondamentaux de la biologie moderne. Avec Pasteur, la vaccination et l’immunologie, on avait découvert les mécanismes de défense contre les infections, c’est-à-dire contre les autres. Nous avons appris depuis un quart de siècle les mécanismes plus complexes et très fondamentaux contre les cellules de l’organisme quand celles-ci s’autonomisent. Au niveau des tissus et du micro-environnement, les voies de communication intercellulaires s’opposent à la prolifération des cellules initiées, notamment par la sécrétion de cytokines. Le système d’immunosurveillance agit en empêchant la prolifération des clones de cellules initiées ou en tuant celles-ci. Inversement, les facteurs de promotion, qui stimulent la prolifération des cellules et/ou altèrent la communication intercellulaire, favorisent la croissance de ces clones jusqu’à ce que de nouvelles altérations du génome rendent les cellules totalement autonomes, parfois leur permettant même de manipuler les cellules qui devraient lutter contre elles, faisant de celles-ci des auxiliaires. Contrairement à ce que l’on pensait, l’accumulation d’un assez grand nombre d’altérations du génome ne peut pas être due au hasard (processus stochastique). Elle est favorisée par des troubles de l’apoptose (qui devrait éliminer les cellules anormales), une instabilité génétique, une stimulation prolongée de la prolifération telle que celles observées après irritation mécanique, une inflammation, une infection ou toute source de dysfonctionnement des systèmes de défense tissulaire. Ainsi, l’émergence d’un cancer n’est pas due seulement à l’induction de mutations dans une cellule; elle nécessite aussi une perturbation du tissu, permettant l’échappement d’un clone de cellules initiées. Cette perturbation peut avoir diverses origines: par exemple une maladie tissulaire (cirrhose de foie, pneumopathie chronique, etc.) ou une désorganisation tissulaire provoquée par la mort de nombreuses cellules, ou la perturbation du dialogue intercellulaire permanent entre cellules au sein du microenvironnement. Le chapitre 5 discute les données cliniques et épidémiologiques. Le chapitre 6 aborde un nouvel aspect de la biologie des tumeurs, celui des cellules souches tumorales. Enfin, le chapitre 7 analyse les voies de recherche. L’épidémiologie montre que les agents de promotion (hormones, alcool, amiante, etc.) sont plus fréquemment incriminés dans la cancérogenèse humaine que les mutagènes; elle montre aussi que le risque cancérogène n’es

Aspects fondamentaux : mécanismes de cancérogenèse et relation dose–effet

Abstract Oncogenesis is a multistep process, which is the outcome of the accumulation in a single cell of genetic and epigenetic events. The events alter proto-oncogenes, which are converted into oncogenes with gain of function and tumor suppressor genes with loss of function. Cellular mechanisms (e.g. apoptosis) protect tissues against the malignant transformation of cells and limit, for each tissue, the combinations of efficient genetic alterations. The number of genetic events required for conversion to malignancy is still debated, but, at least in the case of many solid tumors (e.g. colon carcinomas), this number may be as high as seven to eight, which implies that a genetic instability occurs during cancer progression. In most cancers the probability of occurrence of oncogenic genetic events is increased by exposure to behavioural and environmental factors. In the case of chemical carcinogens, the dose–effect relationship is strongly affected by their effects on cellular proliferation, which should be taken account into when the experimental data of animal experiments are extrapolated to human exposures. When non-genotoxic carcinogens are considered, a threshold in the dose–effect relationship is generaly observed. For genotoxic carcinogens, it is hard to prove experimentally that a threshold exists and linear no-threshold relationships are generally used to evaluate permissible levels of human exposures.