The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer

Abstract

The aim of the present work was to assess the role of monocarboxylate transporters (MCTs), namely MCT1 and MCT4 as well as MCT/CD147 co-expression in gastric tissues and evaluate their clinico-pathological significance in gastric carcinoma. For that, we analysed the immunohistochemical expression of MCT1, MCT4 and CD147, in a large series of gastric samples, including non-neoplastic, tumour and metastatic tissues. A significant decrease in MCT4 plasma membrane expression was observed from non-neoplastic to gastric primary malignant tissues and to lymph-node metastasis and both MCT1 and MCT4 correlated with CD147. Importantly, both MCT4 and CD147 were more frequently expressed in Lauren’s intestinal-type tumours and MCT1/CD147 co-expression was associated with advanced gastric carcinoma, Lauren’s intestinal type, TNM staging and lymph-node metastasis. Our results showed that the prognostic value of CD147 was associated with MCT1 co-expression in gastric cancer cells, supporting the view that CD147 plasma membrane activity is dependent on MCT co-expression.

Introduction

Despite the worldwide decline in incidence and mortality of gastric carcinoma along the second half of the 20th century, it is still the 4th most common cancer and the 2nd leading cause of cancer-related deaths in the world.¹ Prognosis of gastric carcinoma patients depends on several pathological variables. Among them, histological typing seems to have some prognostic relevance. The most prestigious histological classifications include: Lauren’s and World Health Organization (WHO). Lauren’s histological classification identifies two major patterns: intestinal-type (which principally includes papillary, well-differentiated adenocarcinomas, moderately differentiated or mucinous adenocarcinomas without signet ring cell carcinoma (SRC) cells of WHO classification) and diffuse-type carcinomas (usually corresponding to poorly differentiated adenocarcinomas, SRC and undifferentiated adenocarcinomas of WHO classification). This classification distinguishes, by microscopic morphology, two main cancer entities with different clinical and epidemiological features (for review see [2]). The prognosis of gastric carcinoma depends also largely on tumour classification in early gastric cancer, which presents a better prognosis, or advanced gastric carcinoma, with an unfavourable prognosis.³ Although this nomenclature may suggest a progression from one entity to the other, it is still not clear whether these are different stages of the same tumour or independent entities.⁴

Early epithelial carcinogenesis occurs under hypoxic conditions, since altered cells are separated from the vascularised stroma that supplies oxygen and nutrients. To maintain ATP levels, cancer cells increase their rates of glycolysis, developing a significant proliferative advantage. However, this phenotype leads to an overload of lactic acid, which must be expelled out of the cell, causing a decrease in the extracellular pH. Constitutive up-regulation of glycolysis requires additional adaptations, namely, resistance to apoptosis and up-regulation of membrane transporters to maintain normal intracellular pH.⁵ Besides being an adaptation to high glycolytic phenotype, acidic environment represents per se a significant advantage for tumour cells since it is associated with increased migration, invasion and metastases, among others.5, 6, 7 One of the most important groups of proteins involved in intracellular pH regulation is monocarboxylate transporters (MCTs), which are also responsible for transmembrane transport of lactate.⁸ Indeed, there are evidences for the up-regulation of MCTs in tumours, such as high grade glial neoplasms,9, 10 colorectal,11, 12 cervical¹³ and lung carcinomas,¹⁴ but only our studies12, 13 evaluated the clinico-pathological significance of MCT altered expression. Besides an increased MCT expression in colorectal¹² and cervical carcinomas,¹³ we found an association between MCT1 positivity and vascular invasion in colorectal carcinomas¹² and both MCT1 and MCT4 expressions with high risk HPV infection in uterine cervix carcinomas.¹³

MCT expression appears to be influenced by altered physiologic conditions, however, the underlying molecular events involved in MCT regulation are poorly understood. Recently, it was demonstrated that proper expression and activity of MCT1 and MCT4 require co-expression of CD147, also known as EMMPRIN or Basigin.15, 16, 17, 18, 19 On the other hand, silencing studies showed that maturation and cell surface expression of CD147 depend on MCT1 and MCT4 expressions.18, 19 Recently, our group described a close association of both MCT1 and MCT4 with CD147, in cervical cancer.²⁰ CD147 alone has already been described as a key element in oncogenesis by stimulating the synthesis of several matrix metalloproteinases, leading to enhanced tumour cell invasion.21, 22 This protein is described to be up-regulated in human cancers,21, 22, 23 including gastric carcinomas,²⁴ however if its role in cancer is associated with MCTs is not known.

One of the aims of the present study is to assess the role of MCTs in gastric cancer, by analysing the immunohistochemical expression of the MCT isoforms 1 and 4 in a large series of gastric samples, including non-neoplastic, tumour and metastatic tissues, and evaluate its clinico-pathological value. We also intend to infer about the significance of MCT and CD147 co-expression.