Traditional Chinese medicine improves cancer clinical outcome by regulating tumor microenvironment

1. Introduction

The process of tumor formation and progression is influenced by two factors, namely genetic/epigenetic changes in the tumor cells and the rearrangement of the components of the tumor microenvironment (TME) through mutual and dynamic crosstalk. TME consists of tumor cells, tumor stromal cells including stromal fibroblasts, endothelial cells and immune cells like microglia, macrophages and lymphocytes and the non-cellular components of extracellular matrix such as collagen, fibronectin, hyaluronan, laminin, among others. As the heart of TME, tumor cells control the function of cellular and non-cellular components through complex signaling networks to use the non-malignant cells to work for their own benefit. The consequence of such crosstalks is reflected in tumor formation and maintenance as well as deficient response to therapy and multi-drug resistance (MDR). The non-malignant cells in the TME are known to promote tumorigenesis in all phases of cancer development and metastasis.

2. The influence of Chinese herb decoctions on tumor microenvironment

Chinese herb decoctions are prescriptions formulated under the guidance of TCM theory, and are composed of emperor, minister, adjuvant and courier (Jun, Chen, Zuo and Shi) components which may have synergistic effects. Therefore, Chinese herb decoctions regulate the TME as a whole, and intervene through multiple targets. Owen et al. studied the effect of DME-25—an extract of Yangzheng Xiaoji capsules, containing a combination of 16 herbs—on in vitro endothelial cell behavior in the presence of hypoxic lung cancer conditioned medium. The results showed that though avastin could reduce the migration of endothelial cells, this effect was not significant under hypoxia condition. However, when combined with DME- 25, the effect was not impeded by the hypoxia condition. In addition, the effect of avastin on endothelial cell migration was reduced when VEGF was removed under hypoxia; however, it appeared to have little impact on the anti-angiogenic effects of DME-25. Therefore, DME-25 inhibited endothelial cell migration under hypoxia and in the absence of VEGF, indicating that even in the complex TME, it can have an anticancer effect. Min et al. studied the effects of Buyang Huanwu decoction (BYHWD) and its disassembled prescriptions Yiqi decoction and Huoxue decoction on human hepatocellular carcinoma (HCC). They found that BYHWD had no significant growth inhibitory effect on HCC but it may significantly inhibit angiogenesis and metastasis of HCC in nude mice.

The mechanism may be linked to the inhibition of the expression levels of regulator of G protein signaling 5 and hypoxia-inducible factor-1α. However, the level of VEGF expression in HCC was elevated, which conflicted with the traditional view. From this, we may deduce that TCM decoctions inhibit cancers through multiple targets and signal pathways in a synergetic way. In the clinic, Zhang et al. showed the curative effect of the Yiqi Chutan decoction, which was prescribed according to their own clinical experience (banking up earth to benefit metal; Peitu Shengjin). In the transplanted tumor mice model, they also found that the decoction effectively inhibited the tumor growth, and the mechanism may have been related to TAMs. Yu Ping Feng (YPF) decoction significantly inhibited the growth of Lewis lung cancer, prolonged the survival of tumor-bearing mice, promoted NK cell infiltration into tumors, increased the population of NK cells in the spleen and enhanced NK cell-mediated killing activity. Furthermore, YPF significantly downregulated the expression of transforming growth factor-β, indoleamine

2,3-dioxygenase and interleukin-10 in the TME, demonstrating that YPF decoction has a NK cell-dependent inhibitory effect on Lewis lung cancer. Interestingly, Wang et al. found that HY906—a mixture of four herbs: Glycyrrhiza uralensis, Paeonia lactiflora, Scutelleria baicalensis and Ziziphus jujuba—predominantly induced immune suppression and repression of transcription in tumors; the effects were exquisitely tumor-specific when combined with chemotherapy and with irinotecan. It should be emphasized that the advantage of decreasing toxicity in normal tissues while simultaneously promoting cell death in the TME may help TCM be accepted globally.

3. Conclusion and perspectives

TME plays an important role in tumor genesis, development, metastasis and drug resistance,

and its physiological characteristics are significantly different from the microenvironment surrounding normal tissues. Although different tumor cells vary widely and prevention and treatment strategies vary accordingly, the TME in different tumor tissues may have many similarities. Thus, further in-depth study of TME is important for the prevention and treatment of cancer, and the unification of macro- and micro-perspectives. In recent years, TCM has played a more important role in the prevention and treatment of tumor since it treats cancer patients as a whole and achieves satisfactory results. However, the specific mechanisms underlying these effects are poorly understood. Therefore, emphasis on the mechanistic study of antitumor effects from TCM treatments. It is always difficult to study the Chinese herb decoctions mechanistically due to their complex composition. The development of TME may be a good opportunity for TCM to illustrate the advantages of its whole-system and multitarget approach. For this reason, more focus and attention should be invested in the study of Chinese herb monomers and decoctions. Only in this way can we develop an understanding of the exact anti-tumor mechanisms of TCM and provide convincing scientific evidence to promote the broader acceptance of TCM. However, in the study of TCM’s impact on the TME, we should bear in mind the following criteria at all times: firstly, all studies should be designed according to the overall concept of TCM as the guiding theory; secondly, all experimental results should be analyzed in an interconnected and dynamic way; last but not least, we must draw careful conclusions that consider all of the available scientific evidence, with the growing understanding of TME, Chinese medicine research should place more


1. Tumor microenvironment complexity and therapeutic implications at a glance.

2. Progress in research on the effects of traditional Chinese medicine on the tumor microenvironment.

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