**Abstract**

Macrophage polarization is a spectrum of phenotypes and generally can be classified into two states: (1) classically activated or M1 macrophages, which can be driven by lipopolysaccharide (LPS) alone or in association with Th1 cytokines and produce pro-inflammatory cytokines such as TNF-α, IL-6 and, IL-12, and (2) alternatively activated M2 macrophages, which can be promoted by Th2 mediators IL-4 and IL-13 and produce anti-inflammatory cytokines such as TGF-β and IL-10. Current studies have found that the phenotypic switch between M1 and M2 macrophages governs the fate of an organ in inflammation or injury. The imbalance of M1/M2 polarization is closely involved in various pathological processes and is becoming a potential target for therapeutic strategies. Traditional Chinese medicine is an integrated healthcare system composed of many practices and is characterized by multi-target, multi-level, and coordinated intervention effects. Chinese medicines nowadays are applied to regulate phenotype polarization of macrophages to improve the microenvironment, thus ameliorating or even eliminating the symptoms. In this chapter, we will discuss the molecular mechanisms of macrophage polarization, their roles in health and disease, and the intervention with Chinese medicines to modulate the polarization of macrophages in tumor microenvironment (TME) for therapeutic purpose.

**Keywords:** tumor microenvironment, tumor-associated macrophage, polarization, Chinese medicine

## **1. Introduction**

Primary and metastatic tumors are generally known as a complex ecosystem containing tumor cells and the surrounding environment, called tumor microenvironment (TME). Apart from autonomous changes by genetic alteration of tumor cells, the dynamic changes of TME progress the tumor progression [1]. TME is a multifaceted pool that consists of various cell types including neoplastic cells, stromal cells, and immune cells that interact with one another via numerous secreted cytokines, growth factors, and chemokines. Tumor-associated macrophages (TAMs) take up a large portion of recruited immune cells and constitute up to 50% of the tumor mass. It was reported that the high level of TAMs is associated with poor prognosis and decreasing overall survival in many cancers, such as liver, breast, gastric, and thyroid cancers, suggesting that TAMs certainly play essential roles during tumor development [2–6].

TAM recruitment and accumulation are regulated by various cytokines and chemokines, such as CCL2, CCL5, CCL7, CXCL12, etc., and growth factors including VEGF, PDGF, and CSF1, as well as other factors such as fibronectin and fibrinogen [7–10]. CSF1 is the major regulator for monocyte proliferation and differentiation. CCL2 is a dominant attractant in many tumors. Since monocytes highly expressed the receptor of CCL2 (CCR2), most of tumors produced a high level of CCL2 that can intensely attract monocytes migrating toward CCL2-CCR2 axis [11–17]. However, CCL2 inhibition studies show that it could not completely suppress TAM accumulation, indicating that other factors affect this process [7, 17–21]. The CCL12-CXCR4 axis is reported to promote TAM regional accumulation under therapeutic treatments. In mice model, breast cancer highly expressed CCL20 and CCL5; Either inhibited CCL20 expression or treated with CCR5 antagonist, the number of TAMs was significantly reduced within tumors. These studies have shown that in breast cancer, CCL20-CCR6 and CCL5-CCR5 axes contribute to TAM accumulation. Another chemokine CCL11 can be induced under hypoxia condition and subsequently recruit TAMs to the hypoxic region.

In turn, TAMs can produce different molecules to remodel TME and influence fundamental aspects of tumor pathology. For instance, TAMs secrete endothelial growth factor (EGF) to increase neoplastic proliferation directly [22]; TAMs release vascular endothelial growth factors (VEGF) [23], angiogenic factor thymidine phosphorylase, and other chemokines including CCL2 and CXCL8 to enhance angiogenesis; TAMs produce metalloproteases (MMPs) to change TME matrix architecture for tumor metastasis [24]; and TAMs express immune regulatory molecules such as arginase-1 (ARG1), IL-10, and IL12 to modulate immune response [2]. The role of TAMs is accomplished by their phenotypic plasticity, either proinflammatory or anti-inflammatory phenotype, in response to the complex stimuli in TME. The double-edged sword feature of TAM polarization makes them as a novel and potent target for cancer prevention and treatments.

Traditional Chinese medicine is an integrated healthcare system composed of many practices that were rooted in China for over 5000 years. Due to its multitarget, multi-level, and coordinated intervention effects, Chinese medicine is widely used for therapeutic strategies. Recent studies reported that some of the Chinese herbal medicines have beneficial effects on cancer therapy via modulating TAM polarization, indicating a new mechanism for Chinese medicine treatment. In this chapter, we will explore the molecular mechanisms of TAM polarization and their roles in health and disease, and we will review the intervention by some of the Chinese herbal medicines on TAM polarization.

#### **2. TAM polarization and molecular mechanisms**

#### **2.1 TAM polarization**

It is widely accepted that the majority of TAMs are derived from circulating monocytes via cytokine recruitment and then differentiate to macrophages. And those at the metastatic sites are called metastatic-associated macrophages (MAMs) according to their location [25]. While recent studies have shown that the tissue-resident macrophages also contribute to TAM population [26, 27], these

#### *Polarization of Tumor-Associated Macrophages by Chinese Medicine Intervention: Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.86484*

progenitors, also called embryonic macrophages, are derived from the yolk sac or fetal liver-derived progenitors, and they can maintain themselves by local proliferation in a hematopoietic system-independent way [28]. The selective depletion studies found that only the tissue-resident macrophages support the established tumor growth. Therefore, TAMs are heterogeneous cell populations from both tissue-resident macrophages and monocyte-derived macrophages and assist TME remodeling.

Besides their heterogeneity, TAMs are also characterized by high plasticity. In the general regard, macrophages can be overgeneralized to two extreme subsets based on the stimuli, surface markers, and secreted molecules, as well as functional properties: the classically activated M1 and alternatively activated M2 macrophages. The M1 phenotype is induced by the Th1 cytokine interferon-γ (IFN-γ), bacterial moieties such as lipopolysaccharide (LPS), and Toll-like receptor (TLR) agonists. The M1 macrophages are characterized by their capacity to produce inflammatory cytokines (e.g., IL-6, IL-1, IL-12, IL-23, and TNF-α) and stimulate immune response, express reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS), and have a cytotoxic effect toward neoplastic cells and phagocytic microorganisms [29–34]. Generally, the M1-like macrophages act as sentries and display tumoricidal function, antimicrobial activity, and tissue destruction effect [33, 35].

In contrast, the M2 phenotype is promoted by Th2 mediators and produces immunosuppressive factors (e.g., IL-10, TGF-β) and growth factors (e.g., VEGF) and exerts anti-inflammatory and pro-tumorigenic activities [34, 36, 37]. Moreover, the M2-like macrophages can be further subdivided into three categories, M2a, M2b, and M2c, based on the type of stimuli. The M2a macrophages are driven by type II cytokines including IL4 and IL13 and expressed a high level of arginase-1; M2b macrophages are activated by immune complexes/TLR, while M2c macrophages by anti-inflammatory cytokines (e.g., IL-10) and glucocorticoids [38]. The M2-like macrophages promote angiogenesis, wound repair, and tumor growth, as well as resistance to parasitic infection. Many studies reported that TAMs mostly represent M2-like macrophages and play pro-tumoral roles.

### **2.2 Molecular mechanisms in regulating TAM polarization**
