Purpose Increased glycolytic activity with accumulation of extracellular lactate is regarded as a hallmark of cancer. In lymphomas, FDG-PET has undeniable diagnostic and prognostic value, corroborating that these tumours are avid for glucose. However, the role of glycolytic metabolism-related molecules in lymphoma is not well known. Here, we aimed to evaluate the clinical and prognostic significance of a panel of glycolytic metabolism-related molecules in primary non-Hodgkin lymphomas (NHL) and to test in vitro the putative therapeutic impact of lactate transport inhibition. Methods We assessed, by immunohistochemistry, the expression of the metabolism-related molecules MCT1, MCT2, MCT4, CD147, GLUT1, LDHA and CAIX in both tumour and stroma compartments of tissue sections obtained from 104 NHL patients. In addition, the lymphoma-derived cell lines OZ and DOHH-2 were used to evaluate the effect of AZD3965 on their viability and on apoptosis induction, as well as on extracellular lactate accumulation. Results We found that expression of MCT1 in the NHL tumour compartment was significantly associated with a poor clinicopathological profile. We also found that MCT4 and CAIX were present in the stromal compartment and correlated with an aggressive phenotype, while MCT1 was absent in this compartment. In addition, we found that AZD3965-mediated disruption of MCT1 activity led to inhibited NHL cell viability and extracellular lactate accumulation, while increasing apoptotic cell death.Conclusions Our results indicate that elevated glycolytic activity is associated with NHL aggressiveness, pointing at metabolic cooperation, mediated by MCT1 and MCT4, between tumour cells and their surrounding stroma. MCT1 may serve as a target to treat NHL (diffuse large B cell lymphoma) patients with high MCT1/low MCT4 expressing tumours. Further (pre-)clinical studies are required to allow the design of novel therapeutic strategies aimed at e.g. reprogramming the tumour microenvironment.

Introduction: Claudins are tight junction molecules that have been associated with breast cancer prognosis. The claudin-low intrinsic subtype of invasive carcinoma was recently described and associated with high grade carcinoma, low junction molecules expression and worse response to chemotherapy. However, it is not known whether the expression of claudins may provide clues as to carcinoma in situ prognosis. The aim of study was evaluate the association between claudin–4 expression and disease-free survival and histologic type of local recurrence in carcinoma in situ after longer follow up. Methods: A tissue microarray (TMA) block was constructed from 137 pure carcinoma in situ paraffin blocks sampled from patients treated from 1999 to 2009. The TMA was submitted to immunohistochemical staining for claudin-4. A claudin-4 score calculated based on percentage and intensity of expression, categorized samples as: claudin-4-low or claudin–4-high. Clinical data, treatment data, local recurrence data and survival of each patient were reanalyzed from medical records. Kaplan-Meier curves, log-rank and Wilcoxon tests were used to analyze disease-free survival; qui-square and Fisher test were employed to compare others variables; a significance level of 5 % was used. Results: Claudin-4 expression was evaluated in 86 samples, 88.4% were claudin-4-high and 11.6% claudin-4-low. Mean follow up was 8.2 years ( and local recurrence rate was 10.5 %. There was significant difference in the disease-free survival between claudin-4-high and claudin-4-low (4.9 x 1.9 respectively, p= 0.02); however there was no difference between both in histologic type of recurrence, invasive or in situ (p=0.44). Conclusion: In our samples, claudin-4-high expression in carcinoma in situ was more frequent than low expression. Our data showed that claudin-4-low expression had a worse prognosis in carcinomas in situ (inferior disease-free survival) but it was similar to claudin-4-high in histologic type of local recurrence. Citation Format: Duarte GM, Almeida NR, Tocchet F, Espinola J, Pinto T, Barreto CT, Pinto GA, Soares FA, Marshall P, Paiva GR. Claudin-4 expression is associated with disease free survival in breast carcinoma in situ: Mean follow up of 8.2 years [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-05.