In this study, we clearly found that the TSR might be looked upon as a novel biomarker in the predict factor of patients with HCCs after operation. In the present study, patients with a high TSR had a poor prognosis, and patients with a low TSR had good outcomes. Additionally, the TSR in HCC correlated with invasiveness and metastasis. Therefore, the TSR is a significance prognostic factor for patients with HCC who undergo hepatectomy.
In the past studies, TSR has been looked upon as an independent prognostic factor in many other types of cancers. Wang Kai reported that the TSR was an independent element in esophageal squamous cell carcinoma [19]. Van Pelt GW found that the TSR ratio has an important impact on the biological role and prognosis of colon cancer in patients[20]. Roeke. T has used the TSR percentage to predict breast cancer clinical outcomes [21]. The TSR is also widely used in cervical carcinoma [22] and nasopharyngeal cancer [23].
The tumor stroma, including cancer-associated fibroblasts, immune cells[24], epithelial cells, extracellular matrix (EMC) and extracellular molecules, can promote tumor invasion and metastasis[25]. The interactions between stroma cells and tumor cells activate various molecular signaling pathways, which enable these cells to obtain abnormal phenotypes or functional transformations, as well as change the tumor stroma and promote tumor recurrence and metastasis.
Tumor-associated fibroblasts (CAFs) are an important component of the tumor stroma. CAFs can secrete a variety of cytokines, growth factors, and inflammatory mediators that promote cancer cell proliferation, angiogenesis and EMT, ultimately enhancing the cancer’s ability to invade and metastasize. Subramaniam KS has confirmed that CAFs can promote cancer growth via activation of the interleukin-6/STAT-3/c-Myc pathway [26]. Additionally, Carstens JL found that the stroma can affect prostate cancer cell progression by FGFR1-WNT-TGF-β signaling [27]. According to many researchers, CAFs stimulate the proliferation of tumor cells and participate in tumor angiogenesis through TGF-β [28].
In China, patients with HCC mostly develop the disease from hepatitis infection, and they are often diagnosed with liver fibrosis or even cirrhosis. The severity of cirrhosis is significantly correlated with the survival time of patients with HCC after hepatectomy[18]. However, the patient number in our study was too small to reach this conclusion. We hypothesized that patients with severe cirrhosis may have a high TSR and are more likely to experience metastasis, ultimately leading to a poor prognosis. Therefore, TSR analysis for patients with HCC, especially those with fibrosis or cirrhosis, is more important, and the TSR can provide more accurate guidance for the management of patients with HCC after hepatectomy.
Tumor and stromal cells have mutually beneficial interactions. The growth of the tumor stroma provides necessary support for tumor cells, while stromal cells enhance the malignant biological behavior of tumor cells. We speculated that patients with stroma-rich HCC may be associated with EMT, microvascular invasion, and poor prognosis after liver resection. Stroma cells activate EMT and angiogenesis, which enables tumor cells to enter the blood vessels easily, contributing to vascular invasion and other forms of invasion.
Tumor-associated stromal myofibroblasts are essential for the metastatic progression and immune surveillance escape of solid tumors, including HCC [29]. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between PD-L1 and immunity [30].
In this study, in patients with a high TSR, micrometastasis nodules were more likely to be detected by microscopy. Thus, we proposed the following hypothesis: (1) the increased TSR of the TME may promote tumor metastasis because the tumor stroma provides more nutrients and growth factors necessary for migration; the stroma cells also prepare the most appropriate “soil” for tumor cells. (2) Compared with a low TSR, a high TSR may enhance malignant biological behaviors in cancer cells, and these tumors may be more prone to metastasis. (3) The high percentage of stroma may provide greater protection for cancer cells from immune cell killing or enable cancer cells to escape and the immune system and aid in therapeutic resistance. (4) PD-L1 expression on tumor- stroma increased with disease progression. This potential mechanism may account for the poor clinical prognosis in patients with HCC who have a high TSR.
In this research, we can confirm that the TSR is an independent factor predicting outcomes in HCC patients who undergo hepatectomy. PD-L1 expression is related to TSR, and the tumor stromal may provide new target for the HCC treatment. Our research has the following shortcomings. First, our study was retrospective, and the sample size was small. Thus, statistical bias may exist. Second, the TSR cannot be accurately obtained, which may lead to variations among studies.