Police épistémologique : l’enquête « streptomycine »

Pas d’ouvrage de méthodologie des essais cliniques sans une référence historique à la streptomycine. Deux études simultanées, l’une britannique, l’autre américaine, annoncent la médecine moderne : randomisation et rigueur du groupe témoin. Curieusement, la référence citée varie en fonction de la nationalité de l’utilisateur, qui évoque soit le statisticien britannique Austin Bradford Hill, soit la Veteran Administration, et qui élude l’une ou l’autre dans sa bibliographie. L’étude historique permet d’appréhender la lente genèse des essais cliniques et la permanence des difficultés rencontrées dans leur réalisation.The discovery of streptomycin is attributed to a microbiologist, Selman Waksman, Nobel Prize 1952, a paternity that was disputed by his collaborator Albert Schatz, who was the first author of the princeps article. Two pioneering clinical studies involved streptomycin, both of which have been widely used as reference works. The first one was English, under the name of Austin Bradford Hill. It inaugurated a randomization in medicine. The second trial was American, and carried out by the Veteran Administration. It made use for the first time of the « control group ». The present article analyses the genesis of clinical trials and illustrates the recurrent difficulties encountered in their implementation

How to develop better screens for anti-cancer therapies?

The clinical efficacy of chemotherapy relies in part on its ability to potentiate anti-tumor immune responses. Recent work shows that several chemotherapeutic drugs induce intra-tumoral expression of lymphocyte-attracting chemokines, leading to clinical responses. Here, we argue that such knowledge should be used to screen for novel anti-tumor treatments

Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma

International audienceSurgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection

Immune Microenvironment in Tumor Progression: Characteristics and Challenges for Therapy

The tumor microenvironment plays a critical role in cancer development, progression, and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Recent developments in systems biology have improved our understanding of the complex interactions between tumors and their immunological microenvironment in various human cancers. Effective tumor surveillance by the host immune system protects against disease, but chronic inflammation and tumor “immunoediting” have also been implicated in disease development and progression. Accordingly, reactivation and maintenance of appropriate antitumor responses within the tumor microenvironment correlate with a good prognosis in cancer patients. Improved understanding of the factors that shape the tumor microenvironment will be critical for the development of effective future strategies for disease management. The manipulation of these microenvironmental factors is already emerging as a promising tool for novel cancer treatments. In this paper, we summarize the various roles of the tumor microenvironment in cancer, focusing on immunological mediators of tumor progression and control, as well as the significant challenges for future therapies

Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation

International audienceM2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34 -but not CD34 + tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34 -TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34 -TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth

Mosaic DNA imports with interspersions of recipient sequence after natural transformation of Helicobacter pylori

Helicobacter pylori colonizes the gastric mucosa of half of the human population, causing gastritis, ulcers, and cancer. H. pylori is naturally competent for transformation by exogenous DNA, and recombination during mixed infections of one stomach with multiple H. pylori strains generates extensive allelic diversity. We developed an in vitro transformation protocol to study genomic imports after natural transformation of H. pylori. The mean length of imported fragments was dependent on the combination of donor and recipient strain and varied between 1294 bp and 3853 bp. In about 10% of recombinant clones, the imported fragments of donor DNA were interrupted by short interspersed sequences of the recipient (ISR) with a mean length of 82 bp. 18 candidate genes were inactivated in order to identify genes involved in the control of import length and generation of ISR. Inactivation of the antimutator glycosylase MutY increased the length of imports, but did not have a significant effect on ISR frequency. Overexpression of mutY strongly increased the frequency of ISR, indicating that MutY, while not indispensable for ISR formation, is part of at least one ISR-generating pathway. The formation of ISR in H. pylori increases allelic diversity, and contributes to the uniquely low linkage disequilibrium characteristic of this pathogen