[Immunology and personalized medicine in oncology]. / Place de l'immunologie dans la médecine personnalisée en cancérologie.

The comprehension of "what cancer is" was bespoke these two last decades, switching from the traditional centro-cellular vision of cancer to a new holistic vision which integrates the tumor microenvironment and its immune component. Although in both visions, the result is, in fine, the emergence of a clone of cancer cells whose genome is modified, the genesis of the emergence of this clone and of its expansion is quite different offering a new explanatory framework and allowing the design of new predictive bio-markers as well as the development of innovative therapies. Recent data demonstrate that the immune infiltrate of the tumor is determinant for the outcome of patients bearing a solid cancer. For the first time, patient' prognosis can be estimated, not only by the assessment of tumor criteria (TNM classification, genetic disorders) but also by the evaluation of the immune component of the tumor microenvironment, using novel methodologies such as the 'Immunoscore'. Taking account of parameters derived from the reaction of the host against his tumor is an additional step towards a so-called Personalized Medicine in patients with cancer.

[Intratumoral immune microenvironment and survival: the immunoscore]. / Microenvironnement immunitaire et cancer - intérêt de l'immunoscore pour prédire l'évolution clinique.

The natural history of cancer involves interactions between the tumor and the host immune system. In humans, clinical and experimental data support the existence of a natural immune response against cancer. We provided evidence that the type, the density and the location of immune cells within the tumor strongly influence the prognosis, independently of the TNM classification. We established a methodology named "immunoscore" to assess in clinical practice the immune infiltrate. An international consortium of expert laboratories is currently testing the immunoscore in routine clinical settings for cancer classification. The availability of the mmunoscore could significantly improve the prognostic assessment of patients and better guide the therapeutic decision. This could result in the implementation of the immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-immune).

Prognostic and predictive values of the immunoscore in patients with rectal cancer.

PURPOSE: To determine whether the tumor immune infiltrate, as recently evaluated with the Immunoscore methodology, could be a useful prognostic marker in patients with rectal cancers. EXPERIMENTAL DESIGN: The influence of the immune infiltrate on patient's outcome was investigated in patients with or without preoperative chemoradiation therapy (pCRT). The density of total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was evaluated by immunohistochemistry and quantified by a dedicated image analysis software in surgical specimens of patients with rectal cancer (n = 111) who did not receive pCRT and in tumor biopsies performed before pCRT from additional 55 patients. The results were correlated with tumor recurrence, patient's survival, and response to pCRT. RESULTS: The densities of CD3(+) and CD8(+) lymphocytes and the associated Immunoscore (from I0 to I4) were significantly correlated with differences in disease-free and overall survival (HR, 1.81 and 1.72, respectively; all P < 0.005). Cox multivariate analysis supports the advantage of the Immunoscore compared with the tumor-node-metastasis (TNM) staging in predicting recurrence and survival (all P < 0.001). Lymph node ratio added information in a prognostic model (all P < 0.05). In addition, high infiltration of CD3(+) and CD8(+) lymphocytes in tumor biopsies was associated with downstaging of the tumor after pCRT (CD3(+) cells; Fisher exact test P = 0.01). CONCLUSIONS: The Immunoscore could be a useful prognostic marker in patients with rectal cancer treated by primary surgery. The determination of the immune infiltrate in biopsies before treatment could be a valuable information for the prediction of response to pCRT.

Colon cancer at the molecular level--usefulness of epithelial-mesenchymal transition analysis.

Colorectal cancer (CRC) is the third form of cancer in both men and women. In Romania, the incidence of CRC in 2000 is 17.74 %ooo, in 2002 becoming the second cause of death. We reviewed a series of studies that are related to colon cancer and studied the epithelial-mesenchymal transition at the front of tumor invasion (EMT). Cellular phenotypic changes characteristic of EMT can be induced by the absence of transition cofactor (p300) involved in cellular regulation. Loss of syndecan-l marker is associated with local tumor stage and metastasis. Modulators of protein kinase resistance was associated with changes in genes involved in EMT (including vimentin hyperexpression) and genes involved in invasion (N-cadherin) with a decrease expression of genes involved in epithelial cell adhesion (E-cadherin). Progression in colon cancer is characterized by activating mutations in Ras genes and tumor growth factor action. Vimentin expression associated with EMT initiates molecular program. One of the characteristics of EMT is the loss of E-cadherin. TGF-p (transforming growth factor beta) induces epithelial-mesenchymal transition in colon cancer cell lines with the microsatellite stability, inducing cell invasion and migration. EMT is a critical early event involved in invasion and metastasis of colorectal cancer, characterized by the presence of markers specific to each phenotype, epithelial or mesenchymal. Multiple biomarkers involved in the induction of EMT may represent future therapeutic target in the treatment of colonic neoplasia.

Expression of bmi-1 protein in cervical, breast and ovarian cancer.

UNLABELLED: B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-l) is a member of polycomb group, which participates in axial patterning, hematopoiesis, cell cycle regulation, and senescence. Overexpression of Bmi-1 has been reported in various human cancers and proved to be associated with poor survival. DISSUCION: Bmi-I is expressed by various tumors and therefore may contribute to malignant transformation. Bmi-I not only can lead mammary epithelial cells to senescence and immortalization, but also plays a key role in breast cancer. A significant correlation was observed between Bmi-1 expression and axillary lymph node metastases in lymph-ductal breast cancer. Bmi-1 is expressed in cervical cancer and correlated with a poorer prognosis, suggesting that this protein participates in the development and progress of cervical cancer. Regarding ovarian cancer, the results of several immunohistochemical studies revealed overexpression of Bmi-1, especially in poorly differentiated ovarian carcinoma. There is a strong correlation between histological grade, clinical stage and its expression. CONCLUSIONS: Human genes of polycomb group correlated with various hematological and epithelial cancers identify new mechanisms of malignant transformation and pave the way for developing new cancer treatments and identify new diagnostic markers. Bmi-1 and its expression in tissues taken from patients with cervical, breast and ovarian cancer could be a marker for diagnosis and prognosis, and not least a potential target of antitumor therapy.