Depressive symptoms are thought to promote cancer development and depressive remission has been reported to be effective for defeating cancer. The herbal formula Xiao-Chai-Hu-Tang (XCHT), that has an anti-depressive efficacy, has been widely utilized in China. However, its anti-cancer effect and underlying mechanisms remain unclear. The present study aims to investigate the effects of XCHT on the depression-associated tumor and its potential mechanisms. A placebo-controlled trial was conducted in cancer patients comorbid with depressive symptoms to evaluate the effects of XCHT on depressive scales, tumor-related immune indicators, and gut microbial composition. A xenografted colorectal cancer (CRC) mouse model exposure to chronic restraint stress (CRS) was established to examine XCHT effects on tumorigenesis in vivo. Further, by manipulating gut bacteria with fecal microbial transplantation (FMT) or antibiotics-induced bacterial elimination in CRS-associated xenografted model, gut microbiota-mediated anti-tumor mechanism was explored. In cancer patients comorbid with depressive symptoms, XCHT showed substantial effects on improvement of depressive scales, system inflammatory levels and gut dysbiosis. In vivo, XCHT inhibited tumor growth and prolonged survival time in addition to showing anti-depressive effect. Similarly, in our clinical trial, XCHT partially reversed gut dysbiosis, particularly through reducing abundances of Parabacteroides, Blautia and Ruminococcaceae bacterium. Manipulation of gut bacteria in CRS-associated xenografted model further proved that the inhibition of XCHT on tumor progression was mediated by gut microbiota and that the underlying mechanism involves in downregulation of TLR4/MyD88/NF-κB signaling. We demonstrated that gut microbiota mediates the anti-tumor action of the formula XCHT in cancer patients and models that were comorbid with depressive symptoms. This study implies a novel clinical significance of anti-depressive herbal medicine in the cancer treatment and clarifies the important role of gut microbiota in treating cancer accompanied by depressive symptoms.

Colorectal cancer (CRC) is a common malignancy worldwide, and chronic stress has been considered as a significant risk factor for CRC. However, the role of chronic stress in CRC progression is unclear. The present study showed that pre-exposure to chronic stress facilitated CRC tumor growth in mice, and epinephrine promoted CRC cell proliferation in vitro. Metabolomics analysis revealed that chronic stress reshaped metabolic pathways to enhance glycolysis. Additional studies have shown that stress enhanced the expression levels of glycolytic-associated enzymes, including GLUT1, HK2 and PFKP. Mechanistically, chronic stress activated the β2-AR/PKA/CREB1 pathway, as a result, phosphorylated CREB1 transcriptional induced glycolytic enzymes expression. Furthermore, stress-induced cell proliferation and tumor growth could be reversed by administration of glycolysis inhibitor 2-deoxyglucose (2-DG) and β2-AR antagonist ICI118,551, respectively. Altogether, these findings define novel insights into the stress-induced epinephrine-mediated CRC progression from the point of view of tumor energy metabolism reprogramming and provide a perspective on targeting glycolysis as a potential approach in stress-associated CRC treatment.

Brain metastases and related complications are one of the major fatal factors in cancer. Patients with breast cancer, lung cancer, and melanoma are at a high risk of developing brain metastases. However, the mechanisms underlying the brain metastatic cascade remain poorly understood. Microglia, one of the major resident macrophages in the brain parenchyma, are involved in multiple processes associated with brain metastasis, including inflammation, angiogenesis, and immune modulation. They also closely interact with metastatic cancer cells, astrocytes, and other immune cells. Current therapeutic approaches against metastatic brain cancers, including small-molecule drugs, antibody-coupled drugs (ADCs), and immune-checkpoint inhibitors (ICIs), have compromised efficacy owing to the impermeability of the blood-brain barrier (BBB) and complex brain microenvironment. Targeting microglia is one of the strategies for treating metastatic brain cancer. In this review, we summarize the multifaceted roles of microglia in brain metastases and highlight them as potential targets for future therapeutic interventions.

Depression is a risk factor for colorectal cancer (CRC) progression. Xiaoyaosan (XYS) is a traditional Chinese medicine prescription for treating depression. Our present study aimed to investigate the effect of XYS on chronic restraint stress (CRS) in mice with CRC xenografts and explore its underlying mechanisms. XYS treatment for 21 consecutive days successfully reduced the tumour volume and tumour weight in mice and prolonged the overall survival time. In addition, the intestinal permeability in the XYS group was significantly improved after administration. The 16S rRNA high-throughput sequencing method was used to sequence stool samples to check the structure and changes of gut bacteria. XYS mainly regulated the abundance of Bacteroides, Lactobacillus, Desulfovibrio and Rikenellaceae. Taken together, these results provide direct strong evidence that XYS effectively improves the progression of CRC in CRS-handled mice, and its efficacy is associated with the modulation of gut dysbiosis. The application of XYS can be a novel therapeutic strategy for CRC patients with depression.

The tumor immune microenvironment plays a vital role in the metastasis of colorectal cancer. As one of the most important immune cells, macrophages act as phagocytes, patrol the surroundings of tissues, and remove invading pathogens and cell debris to maintain tissue homeostasis. Significantly, macrophages have a characteristic of high plasticity and can be classified into different subtypes according to the different functions, which can undergo reciprocal phenotypic switching induced by different types of molecules and signaling pathways. Macrophages regulate the development and metastatic potential of colorectal cancer by changing the tumor immune microenvironment. In tumor tissues, the tumor-associated macrophages usually play a tumor-promoting role in the tumor immune microenvironment, and they are also associated with poor prognosis. This paper reviews the mechanisms and stimulating factors of macrophages in the process of colorectal cancer metastasis and intends to indicate that targeting macrophages may be a promising strategy in colorectal cancer treatment.

A classic herbal formula San-Wu-Huang-Qin (SWHQ) decoction has been widely used in clinical practices to prevent and treat colorectal cancer (CRC) for years, but its anti-tumorigenic properties and the underlying mechanisms remain undetermined. The present study used a CRC mouse model to clarify whether and how SWHQ suppresses tumorigenesis. Different doses of SWHQ were gavaged to the AOM/DSS model mice to examine its anti-tumor efficacy in comparison with the positive control drug Aspirin. The underlying microbiota-driven anti-tumor action of SWHQ was proven with bacterial manipulations by fecal microbial transplantation (FMT) in vivo and anaerobic culturing in vitro. SWHQ decoction dose-dependently reduced colonic tumor numbers/loads of AOM/DSS models and suppressed their disease activity index scores. SWHQ also recovered epithelial MUC2 secretion and colonic tight junction protein (ZO-1 and claudin1) expression in the mouse model. Such inhibitory impact on tumorigenesis and mucosal barrier impairment was found to be associated with modulation of gut dysbiosis, particularly for suppressing lipopolysaccharide (LPS) producers. The FMT experiment confirmed the substantial contribution of SWHQ-reshaped microbiota to anti-tumor function and mucosal barrier protection. Moreover, LPS-activated TLR4/NF-κB signaling and its downstream pro-inflammatory factors were significantly suppressed in the colon of SWHQ-treated models and SWHQ-reshaped microbiota recipients. We demonstrated that the SWHQ effectively inhibited tumorigenesis and protect mucosal barrier in CRC at least partially by targeting gut microbiota. This study provides scientific basis for the clinical usage of SWHQ in CRC intervention and prevention.