ABSTRACT
Based on the concept of “imbalance of qi movement with the latent cancer toxin”， it is believed that the development process of tumor pre-metastatic niche （PMN） could be summarized as tumor derived secretory factors， exosomes and other “cancer toxin”， which latent in the body， were diffusion-prone by means of meridians and membrane-sources. Besides， the latent toxin induced the imbalance of qi movement， especially the distant weakest qi， and the local sweat pore and collateral vessels were blocked， which resulted in phlegm and blood stasis， and the cross-aggregation of poison. We also proposed therapeutic principles of PMN as first regulating qi and then clearing and expelling toxin， and tried to discuss the theoretical model of traditional Chinese medicine for PMN based on the theory of qi regulation and detoxification， aimed at providing ideas for the future theory construction of traditional Chinese medicine prevention and treatment for malignant tumor metastasis.
ABSTRACT
Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer. Recent research has suggested that cancer cells can also make nanoparticles that also deliver functional molecules in promoting cancer metastasis, which is the leading cause of various cancer mortalities. This nanoparticle is called tumor-derived vesicles, or better-known as tumor-derived exosomes (TEXs). TEXs are nanoscale membrane vesicles (30-140 nm) that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules, including lipids, proteins, and genetic molecules. These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically. More importantly, they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and survival and growth in distant organs. Growing evidence suggests that TEXs play a key role in cancer metastasis. Here, we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability, suppressing systemic immune surveillance, and creating metastatic niches. We will also summarize recent research in targeting TEXs to treat cancer metastasis.
ABSTRACT
The Lewis lung carcinoma (LLC) metastatic mouse model was used to investigate the effects of gefitinib and Sijunzi Tang (SJZ) on pre-metastatic niche. The experimental protocol was approved by the Ethics Committee which belongs to Cancer Hospital, Chinese Academy of Medical Sciences. To generate spontaneous lung metastatic models, 1×106 luciferase-labeled LLC cells were injected subcutaneously in the shaved right flank of mice. One day after LLC inoculation, the mice were randomly divided into model (saline), gefitinib (50 mg·kg-1) treatment, SJZ treatment (25.74 g·kg-1), and co-treatment gefitinib with SJZ groups, with intragastrical administration. After 14 days of continuous administration, tumor size was detected by IVIS® Spectrum system. The number of monocytes and neutrophils and the expression levels of chemokine receptors (CXCR1, CCR2) and carcinogenic gene (c-Kit), in peripheral blood, spleen and lung tissues of mice were determined by flow cytometry. The contents of interleukin-IL-1α (IL-1α) and interleukin-6 (IL-6) were detected by the enzyme linked immunosorbent assay (ELISA). After 21 days of treatment, tumors were surgically removed, weighed and the tumor volume was measured with vernier caliper and the antitumor effect of co-administration was evaluated. After 45 days of administration, the survival of mice was recorded. The results of flow cytometry showed that the percentage of neutrophils in gefitinib group, SJZ group, and co-treatment group was significantly decreased in the lung tissue compared to the model group (P<0.05 or P<0.01), but there was no significant difference between three treatment groups (P>0.05). In the mouse peripheral blood and lung tissue, compared with the model group, the expression levels of CXCR1, CCR2 and c-Kit on the surface of neutrophils and monocytes in SJZ group and co-treatment group decreased or decreased significantly (P<0.01 or P<0.05). However, there was a significant increase in the expression level of c-Kit on the surface of monocytes (P<0.05). In the mouse spleen tissue, the expression levels of CXCR1, CCR2 and c-Kit in the gefitinib group increased significantly (P<0.05), while decreased significantly in SJZ or co-treatment group (P<0.05). The results of ELISA showed that the content of IL-1α in SJZ group decreased significantly in the plasma of the mice compared with the model group (P<0.01) and the content of IL-6 in co-treatment group decreased significantly (P<0.05). Compared with the gefitinib group, the content of IL-1 in the co-treatment group decreased significantly (P<0.05). In the tumor tissues of mice, compared with the model group, the content of IL-1α in the co-treatment group decreased significantly (P<0.05). Furthermore, the content of IL-1α in co-administrated group and IL-6 in SJZ or co-treatment group decreased significantly compared with the gefitinib group (P<0.05). After 21 days of continuous administration, the tumor inhibition rates of gefitinib group, SJZ group and co-administrated group were 45.7%, 38.4%, and 84.8%, respectively. After 45 days of administration, the survival rate of the model group was 0%, whereas the gefitinib, SJZ or co-treatment group has a survival rate of 40%, 60%, or 60%, respectively. In summary, our study illustrated that Sijunzi Tang could improve the anti-tumor effect of gefitinib by regulating pre-metastatic niche.
ABSTRACT
The tumor-associated neutrophils (TANs) are thought to be important and complicated character in tumor microenvironment.TANs play dual roles of anti-tumor or tumor-promoting in tumor microenvironment under different factors.TANs can not only play the anti-tumor effect by killing tumor cells directly and promoting immune response,but also can act as tumor promotors by promoting tumor angiogenesis and mediating tumor invasion and metastasis.Recent researches find that TANs are closely related to pre-metastatic niche (PMN),which can promote the construction and maintenance of PMN by means of changing the content of cell factors like interferon-γ.