Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells.

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVß1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFß at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.

Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy.

PURPOSE: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3'-untranslated region (3'-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer. EXPERIMENTAL DESIGN: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3'-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3'-UTR region polymorphisms was evaluated and a haplotype analysis was performed. RESULTS: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P < 0.01). The TYMS promoter and TYMS 3'-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3'-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy. CONCLUSIONS: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.

Matrix metalloproteinase 3 polymorphism: a predictive factor of response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma.

PURPOSE: Treatment of head and neck cancer often associates different therapeutic modalities, including surgery, radiotherapy, and chemotherapy. In an attempt to optimize therapeutics, the identification of molecular markers linked to response to chemotherapy remains important. Recently, the involvement of metalloproteinases in resistance to chemotherapy was suggested through their interaction with the Fas/Fas ligand pathway. Indeed metalloproteinases enhance Fas ligand shedding modulating chemotherapy efficiency. On the basis of these findings, we tested the existence of a correlation between response to chemotherapy and four metalloproteinase polymorphisms in a prospective series of 148 head and neck cancer patients. EXPERIMENTAL DESIGN: Patients were genotyped using automated fragment analysis and 5'-nuclease allelic discrimination assay. Response to chemotherapy was clinically assessed without knowledge of the genotype status. RESULTS: A significant relation between the metalloproteinase type 3 (MMP3) -1612insA polymorphism and response to chemotherapy was identified. Indeed, patients with the 6A/6A genotype responded more frequently (86%) to treatment as compared with patients with the 5A/6A (65%) or 5A/5A (55%) genotypes (P = 0.04). A multivariate analysis, including tumor stage, gender, TP53 mutations, and MMP3 polymorphism, showed that the 6A/6A genotype was an independent factor of response to 5-fluorouracil-cisplatin chemotherapy in head and neck cancer patients with an odds ratio of 6.7 as compared with the 5A/5A genotype. CONCLUSIONS: This work showed that genotyping the MMP3 gene enhancer polymorphism -1612insA could help predict chemosensitivity in head and neck cancer patients.