In this study, MCT1, MCT4 and IL7R expression were shown to be strikingly predominant in the stroma of ESCC tissues; and that over-expressed MCT1, MCT4 and IL7R were found to be significantly linked with T classification, lymph nodes metastases and distant metastases. Moreover, these three biomarkers were analyzed to be independent prognostic factors in ESCC, strongly suggestive of their prognostic value in ESCC.
As numerous studies have probed the biochemical or mechanistic roles of MCT1, MCT4 in the setting of cancer from different tissue origins, our aim here was not to explore their working mechanism but to analyze the clinicopathological implications of their expression in ESCC. Immunohistochemical characteristics were quantitatively analyzed of ESCC cells expressing MCT1, MCT4 and IL7R, exhibiting that immunostaining of MCT1, MCT4 and IL7R were observed mainly on cytoplamsic membrane and slightly in cytoplasm. In order to analyze the correlation between these three markers we take interested in, four sets of ESCC tissue microarrays were used on which dots of each set were entirely obtained from the same site of tissue serially sectioned. To rule out the possibility that the three biomarkers could be expressed by other types of cells, other than ESCC cells we focused upon only, within the tumor microenvironment; Hematoxylin and eosin (H&E) staining was performed and frequently reviewed when immunoscoring. Given this, the expression of MCT1, MCT4 and IL7R was thus unlikely to be overestimated in ESCC tissues in our setting.
MCT1, also known as SLC16A1, has been reported to take charge of influx of lactate. In stark contrast, physiologically, MCT4 was found to be in charge of efflux of lactate, as systemically reviewed by Halestrap AP. Although extensive studies can be readily available regarding the MCT1 in cancers of different types; it has been little described in esophageal cancer with the exception of two recent related reports[17, 18]: one about MCT1 expression in Barrett's esophagus and adenocarcinoma, the other ESCC. Analysis from previous investigations concerning MCT1 in cancers, regardless of different types[19-22], revealed that MCT1 prevailed or predominantly over-expressed in cancerous tissues as compared with normal controls and up-regulated MCT1 was found to be linked with poor outcome as well as tumor metastases, which was fully in agreement with our observations in ESCC of our own case. What’s congruent with our description with regard to MCT1 is that, in a recent study  by Chen X and colleagues, MCT1 was exhibited to be an independent prognostic factor in ESCC. What’s different from the study by Chen X et al  in that, there was short of functional analysis data of MCT1 in our setting with cell culture system. Examination of data from these aforementioned literatures along with our own findings about MCT1 in ESCC, explicitly suggested the prognostic value of MCT1 in malignancies, irrespective of their types.
Much like MCT1, MCT4 comes from the same family as MCT1 does. But, in the case of mediating the lactate transport, it was totally opposite of MCT1. MCT4 was mainly involved in the release of lactate or “efflux”, whereas uptake of lactate or “influx” was chiefly mediated by MCT1, as extensively reviewed[1, 23]. Relative to the quantity of studies of MCT1, MCT4 seemed to be received more attention than those of MCT1 in cancer. Studies undertaken in the area of cancer abound, unraveling that MCT4 was uniformly seen to be strikingly up-regulated in cancerous tissues compared with normal control; and elevated MCT4 was correlated with unfavorable outcome [19, 21, 24-26]. By contrast, there were only two pieces of literature with regard to MCT4 in esophageal cancer until now[17, 27]. In our findings, MCT4 was exhibited to be an independent prognostic factor of ESCC, whereas no significant correlation with lymph nodes metastases was observed, was partly supported by the replicated observation made by Cheng B et al in ESCC. Moreover, we also noted that MCT4 expression was found to be closely related with tumor size, as MCT1 was. It may be that more lactate transporters could be needed so as to suit the metabolic reprogram with the development and progression of ESCC cells.
Scant data has been available on the clinicopathological implications of IL7R in solid tumors, not to mention in ESCC; although several lines of evidence existed concerning genetic polymorphisms or mutations of IL7R in the context of hematopoietic lymphoma. IL7R was not necessarily expressed in immune cells; it can also be expressed in cancer cells, such ESCC cells  and hepatoma cells . Although there was one similar study has been replicated regarding IL7R in ESCC; the clinicopathological involvement of IL7R currently remains unknown. In our study, IL7R was shown to be over-expressed in ESCC tissues relative to paired normal controls, which was highly consistent with what has been reported by Kim MJ and associates. Unfortunately, there has been a shortage of clinicopathological analysis of IL7R expression in their study. Hinted from the limited data available in the above studies, these findings suggest that IL7R can work oncogenically in malignant tumors. Our observation that up-regulated IL7R was closely linked with clinical stage and shorter overall prognosis, further supports the oncogenic function of IL7R in tumors.
Current opinion holds that Inflammation is associated with the accumulation of lactate at sites of tumor-growth. Several tumors and inflammatory sites have displayed accumulation of lactate and altered expression of its transporters, which is strongly suggestive of the heavy involvement of lactate transporters in cancer and inflammation. In our study, despite we failed to analyze the lactate concentration on the ESCC tissue microarray that we used to concomitantly assess the expression of MCT1, MCT4 and IL7R owing to the technical limitation; over-expressed MCT4 can mean the release of lactate would be much more active than it should be. As a result, there will not be surprising that more lactate released from ESCC cells could stimulate inflammatory microenvironment in a way, thereby contributing to the up-regulation of IL7R of ESCC cells. More recently, a piece of evidence showing that lactate production was dramatically enhanced after colorectal cancer cells were treated with IL6 , strengthens the conjecture we raised here. Based on the observation, it can be safely reasoned that elevated IL7R may also boost the lactate yield in ESCC cells, which consequently may require more lactate transporters, such as MCT1 and MCT4, in order to suit any variation caused by lactate in tumor microenvironment. Of course, the hypothesis we posed here needs to be tested experimentally in the following. On the other hand, in consideration of lymphocyte that infiltrates the ESCC tissues can also express these three markers, it is therefore somewhat difficult to control the real expression of MCT1/4 and IL7R only in ESCC cells. As for the lymphocyte that infiltrates the ESCC tissues that may also express MCT1/4 and IL7R, which beyond the scope of our investigation.