Traditional Chinese Medicine (TCM) Plays A Pivotal Role In Regulating Tumor Microenvironment

Lung cancer is the most common cause of cancer-related deaths in men and women globally and with the highest rate of morbidity and mortality. In 2014, about 1.5 million new patients were diagnosed worldwide and approximately 1.6 million die of this disease every year. Non-small-cell lung cancer (NSCLC), accounting for 80% of lung cancer, has a dismal five-year survival at 15% and even worse, patients with advanced NSCLC, if left untreated, have a median survival of 4-5 months after diagnosis. During the past decades, new treatments, such as minimally invasive, surgery, targeted therapy, adjuvant chemotherapy, and individualized therapy, have been applied but have a less important effect in improving the overall 5-year survival, especially in the advanced stage. Nonetheless, all above therapies have focused on tumor cells.

However, uncontrolled growth in tumors, invasion, and metastasis cannot be elucidated solely by aberrations in cancer cells themselves. Over the past few decades, a major paradigm shift happens to cancer therapy and a great deal of effort has been put forth to develop therapies that target the tumor microenvironment. Accumulating evidences suggest that the alterations that occur in the stroma around a tumor prove useful in antiangiogenesis, antitumor metastasis, and prognosis. Nontumoral cells, including stromal cells (fibroblasts, endothelium cells, etc.) and leukocytes, are a prominent component of solid tumors. Tumor-associated macrophages (TAMs), an important component, acquire a distinct, tissue-specific phenotype in different microenvironments and have both anti- and protumor effect due to two distinctly different polarization, respectively, referred to as “classical” (or M1) and “alternative” (or M2) activation. In tumor microenvironment, TAMs are primarily polarized toward a M2-like phenotype, which have the ability to promote the growth and vascularization of tumors. Collective evidences demonstrate that the dual roles of TAMs have been demonstrated both in vitro and in vivo in different tumor models. Moreover, clinical studies make strong cases that TAMs, characterized by M2 phenotypes, are poor predictors of prognosis and progression in numerous malignancies.

TAMs also profoundly influence the effects of conventional treatment modalities (chemotherapy and radiotherapy), targeted drugs, antiangiogenic agents, and immunotherapy, including checkpoint blockade. Therefore, TAMs are essential for effective therapy and M2-like TAMs are considered to be potential target for adjuvant anticancer therapies. In addition, extensive studies have been carried out to declare that approaches targeting M2-like TAMs have gained encouraging results. Thus there is a growing appreciation that skewing TAM polarization away from the M2- to M1-like phenotype is of great importance.

Accumulated data indicates that traditional Chinese medicine (TCM) plays a pivotal role in regulating tumor microenvironment, including remodeling immunosuppressive microenvironment, hypoxia microenvironment, angiogenesis/lymphangiogenesis, and extracellular matrix. Qing-Re-Huo-Xue (QRHX) formulae consist of a 1 : 1 mixture (w/w) of Radix Paeoniae Rubra and Scutellaria baicalensis. The above formula is frequently used in treatment of chronic inflammatory diseases in the respiratory system and immunocompromised diseases in TCM. Increasing evidence revealed that QRHX and its components, extracts, and derivative have the ability of anticancer and anti-inflammation. Nevertheless, there are no reports which concerned the alleviated effects of QRHX on macrophage-mediated lung cancer. In the present study, we aimed to investigate the relevance between macrophage polarization and the antitumor effect of QRHX in mice.

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