| The liver is vital to vertebrates and some other animals and it is one of the largest solid organs in the human body. It helps to filter harmful substances from blood, store glycogen for the use of energy, and make bile to digest fat. The liver has been proposed as one of the immune organs in the human body. Liver has many unique immunological properties, although the primary functions of the liver are not immunological, it performs many essential immune tasks. Its unique structure gifts liver with its unique immune functions. In addition to local immune responses, liver may also regulate systemic innate immune responses, which makes it especially important in battling with pathogens, parasites, and the invasion of malignant cells.The liver is highly specialized tissue consisting of mostly hepatocytes. But recent studies have revealed high percentage of NK cells, NKT cells and macrophages in the liver. The liver contains the largest population of resident macrophages (Kupffer cells), which accounts for 80-90% of all fixed tissue macrophages in the body. In addition, the liver also contains a large number of infiltrating monocytes/macrophages, especially during liver injury and infection.Adult primary liver cancer, including HCC and cholangiocarcinoma, is now the second leading cause of cancer-related deaths worldwide. HCC constitutes the majority of the malignancy in the liver, it is often caused by common clinical risk factors such as chronic viral infection with HBV and HCV, heavy alcohol intake, stcatohepatitis, and diabetes. Most of HCC incidences are a consequence of chronic viral infection with HBV and HCV that develops into persistent inflammation, resulting in fibrotic and/or cirrhotic liver with extensive leukocyte infiltration. Crosstalk between different cell types within the tumor and its stroma often results in tumor progression. Nowadays, hepatic resection is still considered as one of the most effective therapies to treat HCC, however, the overall post-surgery survival of HCC patients remains unsatisfactory due to high recurrence rate.1. CD200R predicts the prognosis of human hepatocellular carcinoma.The immune system has developed sophisticated ways to balance its responses and tolerance. On one hand, the immune system identifies and eliminates tumor cells expressing foreign antigens, while on the other hand, it controls its responses from attacking cells expressing self-antigens and maintains tolerance. Cancer cells find their way to escape from this system and avoid immune attacks. The underlying mechanisms of immune escape have been extensively studied, one of which is the manipulation of immune checkpoint molecules that are induced upon cell activation. It is believed that during the progression of cancer, immune cells become exhausted and less/null functional, making tumor cells easier to escape from immune responses. The exhaustion of immune cells is usually accompanied by high expression of co-inhibitory molecules, the manipulation of these negative regulators may restore immune responses to fight against tumor cells.The inhibitory CD200:CD200R axis is essential in preventing inflammatory responses and immune pathology during early microbial infection. It was reported in several tumor models that CD200 expression is associated with tumor progression and the blockade of this pathway may restore anti-tumor responses. CD200 is broadly distributed in a variety of cell types, including solid tumors and hematologic malignancies, while its receptor, CD200R, is primarily expressed on myeloid-derived and lymphoid-derived immune competent cells. CD200-CD200R axis seems to benefit tumor cells and the inhibition of immune responses. Since CD200-CD200R axis inhibits immune responses in several tumor models and either directly or indirectly interferes with the activity of immune cells, we investigate the possibility of CD200-CD200R axis in association with HCC.Not surprisingly, we found elevated expressions of both CD200 and CD200R in HCC patients compared with healthy controls. In concordance with previous researches, we observed that CD200R mainly expresses in immune competent cells while CD200 is broadly distributed in various liver cells and cancer cells. Peritumoral stroma region is also known as the invasive margin (IM), it connects the core of the tumor (intratumoral region) and the distant liver stroma (peritumoral region). Crosstalk between different cell types within the tumor and its stroma is now well recognized as one of the causes of tumor progression. Peritumoral stroma is often enriched with infiltrating leukocytes and can be easily identified under microscope. CD200R predominantly expresses in peritumoral stroma region, where most infiltrating leukocytes are presented, suggesting a possible role of CD200R in suppressing these CD200R+ infiltrating leukocytes.In addition to the immunostained observations, IOD/area was computed as a measure of expression in HCC patients. Higher IOD/area implies higher expression and vice versa. IOD/area of CD200R is positively associated to the tumor diameter and AFP level, and HCC patients with advanced cancer or loss of tumor capsule exhibit significantly higher CD200R expression in their peritumoral stroma than patients with tumor capsule or in early stage, all of which indicates that CD200R expression accumulates along tumor progression and may be used as a prognostic marker in predicting the development of tumor itself.Although cancer patients are well-known with a generalized immunosuppressive status, substantial evidence has indicated that the inflammatory reaction at a tumor site may promote tumor growth or progression. HCC is often induced from inflamed cirrhotic liver with extensive leukocyte infiltration, among the infiltrating leukocytes, macrophage-lineage kupffer cells are often enriched predominantly in peritumoral stroma, with only few macrophages present within HCC tumor itself. Immunohistochemical staining of CD8, CD57 and CD68 on consecutive sections re-confirms the massive presence of infiltrating CD68 macrophages in HCC tissues. In addition, the majority of CD200R+ cells co-localize with CD68+macrophages, confirming the expression of CD200R on CD68+ macrophages in this particular case.Notably, HCC is different from other malignancies because the prognosis of HCC is not only dependent upon the tumor stage but also on the function impairment due to accompanying cirrhosis. Therefore we further investigated the role of CD200R in liver injury. Basic comparison between CD200Rhlgh and CD200Rlow shows elevated AST levels in patients with higher CD200R expression.Human HCC often accompanies high rate of tumor recurrence and metastasis, thus, it is urgent to identify prognostic biomarkers for the prediction of potential recurrence and metastasis. In our study, it was found that both overall and recurrence-free survival rates are significantly lower in patients with high CD200R expression than in patients with low CD200R expression, suggesting a promising role of CD200R in predicting elevated recurrence and reduced survival in HCC patients.CD200R signaling enhances tolerance and inhibits immune responses in HCC, blockade of which may reverse the negative regulation of immune cells and restore anti-tumor responses, suggesting its promising role in enhancing the efficacy of immunotherapy. However, an important aspect to note is that CD200R signaling not only inhibits immune responses, it also inhibits pro-tumorigenic inflammation at the same time. Blockade of CD200-CD200R interaction enhances anti-tumor responses but also increases pro-tumorigenic inflammation that may result in tumor progression. Thus, pro-tumorigenic inflammation needs to be concerned when using CD200R checkpoint blockade and it is important to find the balance in order to block this pathway for further clinical usage.Collectively, we for the first time demonstrate that peritumoral stroma CD200R may serve as a potential indicator in predicting the progression and prognosis of HCC, patients with high density of CD200R are likely to suffer from a more severe malignancy condition, accompanied by elevated recurrence and reduced survival. Since the efficacy of current systemic therapies for HCC is limited, CD200R may be considered as an effective therapeutic target in treating HCC. Yet, detailed underlying mechanism merits further research and more comprehensive studies are needed to reach the step.â…¡. Decreased expression of MARCO is associated with the progression and prognosis of human hepatocellular carcinoma.Innate immune cells recognize pathogens through pattern recognition receptors (PRRs), which include scavenger receptors (SRs). The class A SR family and Macrophage Receptor with Collagenous structure (MARCO) are characterized by the presence of collagenous and SR cysteine-rich domains in their extracellular portions. Both receptors are expressed predominantly on macrophages and dendritic cells, and function as molecular sensors on various cells types and act as phagocytic receptors binding to a variety of microbial components. However, several clues indicate that SRs may function more than pattern recognition and phagocytic clearance. MARCO expresses on restricted subsets of macrophages and its expression can be induced at sites of inflammation after bacterial infection. It seems to play a role in inflammatory and immune responses other than the typical functions of macrophage recognition and clearance of pathogens and their polyanionic ligands.Nowadays, the role of MARCO is still debating and barely any research has been done to study the expression of this molecule and the progression of solid tumor. However, interestingly, RNA-Seq analyses of human hepatocellular carcinoma (HCC) have revealed MARCO as one of the top 30 differently expressed genes between HCC and adjacent non-cancerous tissues. In addition, liver is enriched with kupffer cells which are the predominant site of MARCO expression. It raises the question whether MARCO can be a potential prognostic indicator for HCC and other liver diseases?Since human livers are rich in innate immune leukocytes such as NK cells, NKT cells and macrophage-lineage kupffer cells, given the existing evidence that MARCO highly expresses on macrophages, we investigated the role of MARCO in liver. Interestingly, publicly available gene expression data showed that mRNA expression of MARCO in normal liver tissues is significantly higher than that in HCC (Oncomine, www.oncomine.org).In our study, in addition to the immunostained observations, IOD/area was analyzed as a measure of protein expression of MARCO. Higher IOD/area implies higher expression and vice versa. In accordance with the conclusion from the gene datasets, we found in our samples that both the protein and mRNA expression levels of MARCO in the peritumoral tissues are significantly higher than those in the intratumoral tissues. Furthermore, the highest expression of MARCO was found in healthy controls, followed by patients with liver cirrhosis, patients with HCC, and lastly patients with HCC metastasis, which again agrees with the conclusion from gene datasets. One thing to note is that there was a clear boundary between the peritumoral and intratumoral tissues in the peritumoral stroma area, considering that only few macrophages reside within the HCC tumor itself, we found clear discrimination in the MARCO expressions. The MARCO expression of healthy controls is significant higher than that in HCC tumors or HCC metastases, although comparisons between other groups showed no statistical significance, a clear tendency may be observed to suggest that the expression of MARCO reduces progressively as the disease condition aggravates.MARCO not only reduces along disease aggravation, from our results, we found that MARCO also reduces along tumor progression. It was found that MARCO expression of patients in the early TNM stage is significant higher than patients in the late TNM stage, and MARCO expression in patients with tumor capsule is higher than those without tumor capsule, in which the two parameters are often associated with the severity of the cancer. These data suggest that MARCO reduces along disease and tumor progression and may be used as a prognostic marker in predicting the development of liver diseases.Although the peritumoral tissues are considering "normal" comparing to the intratumoral tissues, most of them are in fact suffering different degree of inflammation. Kupffer cells are liver-resident macrophages that largely contribute to inflammatory reactions in the liver. A co-localization of CD68" macrophages and MARCO+ cells confirmed their predominant expression on macrophages.Human HCC has a high rate of tumor recurrence and metastasis, which results in lower overall survival rate. In our study, it was found that the overall survival rate is significantly higher in patients with high MARCO expression than in patients with low MARCO expression, suggesting a promising role of MARCO in predicting elevated survival in HCC patients.Collectively, our study is the first to illustrate the relationship between MARCO and HCC. In particular, our findings suggest that patients with low MARCO expression show a more severe malignant condition accompanied by reduced survival. Although the study itself was simple, we provide solid evidence on a new topic that has not previously been investigated. However, whether the low expression of MARCO in HCC patients is causative or simply a result of their poor prognosis remains unknown. On the one hand, given that MARCO is mainly expressed on macrophages and few macrophages reside within the HCC tumour itself, it is possible that the intensity of MARCO expression decreases because of the decreased number of macrophages present in the intratumoural region. On the other hand, however, we cannot exclude the possibility that macrophages may be altered when the MARCO expression level changes, and how these altered MARCO+ macrophages contribute to tumour progression remains unknown. Thus, the detailed mechanisms underlying the MARCO-HCC axis necessitate further research, and substantial prospective studies are required to confirm the prognostic role of MARCO. |
PDF Full Text Request