The liver is the most frequent site of hematogenous metastasis in GC, and the patients usually have dismal prognosis when diagnosed with GCLM . Considering that liver metastasis commonly accompanies with simultaneous peritoneal and distant lymph node metastases, the guideline recommends chemotherapy instead of surgery as the first-line treatment for GCLM [3, 22]. The famous seed and soil hypothesis proposes that only the microenvironment that has acquired the capacities of engraftment, survival support and immune evasion could become a new metastatic target organ . In the process of cancer metastasis, cancer cells first form micrometastases in distant metastatic organs and then proliferate into visible metastases. The specific organ microenvironment can promote the colonization, survival and proliferation of tumor cells. However, lack of research shed light on the liver microenvironment (soil) in GCLM. To early detect the high-risk individuals of synGCLM, the study intented to declare whether liver disease would remodel its microenvironment to become a fertile, premetastatic soil for GC cells (seed) to land and proliferate. Here we conducted a retrospective study to demonstrate the impact of HBV infection on the metastatic pattern of GC.
We found that the prevalence of HBsAg+ was 6.9% among all the GC patients, in accordance with that in the general population in China . The prevalence of synGCLM in our study was 8.8%, which was also consistent with that reported by previous studies . Results illustrated that the prevalence of synGCLM in the HBsAg+ patients was 16.7%, significantly higher than that of 8.2% in the HBsAg– patients (P = 0.025). As HBV infection affected the metastatic pattern of tumor, a study in Italy reported that the presence of HBsAg in patients with colorectal carcinoma significantly increased the incidence of liver metastasis recently . Meanwhile, with the stimulation of HBsAg, interleukin (IL) -10, IL-12 and interferon (IFN) λ could be produced by dendritic cells, which played a vital role in the progression of HBV-related tumor . Moreover, HBV-encoded X protein (HBx), as the only one protein encoded by the HBV genome and expressed by transformed hepatocytes, could affect differentiation and promote tumor progression metastasis, which proved by the positive cross-talk with the metastasis-associated 1 (MTA1) in stabilizing hypoxia-inducible factor (HIF)-1α [25, 26]. Experiments in vivo and vitro also proved that HBx could promote tumor invasion by up-regulating matrix metalloproteinases (MMPs) and cyclooxygenase (COX)-2, which provides new insights into its involvement in tumor metastasis and recurrence . Also, HBx could up-regulate long non-coding RNA MALAT1 and further activate LTBP3, which resulted in the development and metastasis of tumor . Furthermore, the transforming growth factor (TGF)-β production stimulated by HBx could promote Treg cell recruitment, which maintained a tolerogenic liver microenvironment and finally induced the development of metastasis [29, 30]. These above mechanisms may explain how HBV infection adjust the liver microenvironment becoming a premetastatic niche (soil) for circulating tumor cells (seed) to colonize. Besides, a study conducted by Wei verified the objective evidence of the existence of HBV infection in GC tissues, it proposed that HBV infection was a possible significant predictor for the development of GC . The influence of HBV infection on both GC tumor cells and liver microenvironment may mediate GC metastasis, and the interaction between tumor cells and liver microenvironment need to be further investigated.
Inspired by the classic hepatitis-cirrhosis-HCC pathway , we further investigated whether liver fibrosis/cirrhosis related to HBV infection influenced GCLM. As liver biopsy was seldom utilized in clinical work, we used the noninvasive liver fibrosis model to assess the degree of liver fibrosis in the 60 GC patients infected with HBV. Due to ARPI and FIB-4 were both efficient indexes used to evaluate the degree of HBV-related liver fibrosis, which took the factors like the age, platelet, AST, ALT of patients into consideration, and widely available in the clinical setting . The study demonstrated that both the median of ARPI and FIB-4 in the HBsAg+ patients with synGCLM were significantly higher than those among the HBsAg+ patients without synGCLM. HBeAg positivity in HBsAg+ patients with synGCLM was higher compared with that in HBsAg+ patients without synGCLM, although the difference was of no significance. A study conducted by Chiou in Taiwan drew a similar conclusion that cancer patients with liver cirrhosis had a higher risk for liver metastasis in colorectal cancer . Another study from China also reported that fibrosis niche might be a favourable microenvironment for the formation of hepatic metastasis based on noninvasive liver fibrosis scores . The phenomenon may be resulted from local microenvironment change and immune reaction alteration. The continuous production of HBsAg can cause persistent HBV infection-associated inflammation, which accompanied by the transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts. At the meantime, these fibroblasts will propagate, along with the deposition of the extracellular matrix, consequently lead to liver fibrosis even cirrhosis [36-38]. On the other hand, as the component of prometastatic liver microenvironment, HSC can promote tumor growth, facilitate tumor invasion and suppress the anti-tumor immune response . Moreover, the angiogenic factors such as vascular endothlial growth factor (VEGF) and angiopoietin 1 in liver fibrosis environment could promote tumor angiogenesis . In conclusion, more animal experiments and prospective clinical trials need to dig into the underlying mechanism of the cirrhotic microenvironment and active virus replication in the metastasis of GC.
There were several limitations in that it was a retrospective, cross-sectional study conducted in only one single center. The comorbidities like diabetes, obesity and the HBV-DNA level of all patients were insufficient. And liver fibrosis/cirrhosis was measured by ARPI/FIB-4, other than a liver biopsy. Despite these limitations, our study still enrolled a large number of newly diagnosed GC patients, and all with information about hepatitis B status. Moreover, our study investigated the effect of HBV infection only on synchronous liver metastasis, to avoid the interference of different anti-cancer treatments among GC patients and imprecision information about metachronous metastasis. Besides, our study was the first study that demonstrated the impact of not only HBV infection but also HBV-related cirrhosis on liver metastasis formation and survival in GC. Overall, our study discovered that HBV infection and HBV-related cirrhosis might remodel the liver microenvironment, becoming a premetastatic niche for GC cells to proliferate. This unique and exciting information may provide novel anti-cancer treatments on blocking premetastatic niche formation (soil) to prevent liver metastasis and even cure gastric cancer metastasis in the future. More prospective studies with larger sample size and animal experiments are needed to validate our findings and further explore the cause-effect relationship between HBV infection and synGCLM.