Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation

Abstract

Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment.

Keywords: colorectal cancer; macrophages; polarization; role of SRIF system in immune system; somatostatin; somatostatin receptors; tumor-associated macrophages.

Figure 1

Signaling molecules regulating macrophage polarization in CRC: Undifferentiated macrophages (M0) can be polarized into two types: classically activated macrophages (M1) and alternatively activated macrophages (M2). The polarization of TAMs into M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor) phenotypes is a highly dynamic process, influenced by a complex interplay of factors within the TME. The figure depicts the different signaling molecules—proteins/extracellular vesicles, colonic microbiota components/natural bioactive compounds, and ncRNAs (lncRNAs and miRNAs)—that play a crucial role in the regulation of macrophage polarization and activation. The cytokines responsible for M1 and M2 polarization are also shown. [(+)/(−)—positive/negative regulation; AI-2—F. nucleatum autoinducer-2; A. muciniphila—Akkermansia muciniphila; ARCR—Astragalus mongholicus Bunge-Curcuma aromatica Salisb; BBR—berberine; CB1—cannabinoid receptor 1; CPEB3—cytoplasmic polyadenylation element binding protein 3; Cp (Nem)—Cuban brown propolis (nemorosone); CRC-EVs—colorectal cancer-derived EVs; CTSK—metastasis-related secretory protein cathepsin K; E. coli—Escherichia coli; EGFR—epidermal growth factor receptor; EVs—extracellular vesicles; F1-MEV—F1 fraction of scorpion venom from Mesobuthus eupeus; F. nucleatum—Fusobacterium nucleatum; HMGA2—high mobility group A2; IFN-γ—interferon-gamma; IL-4/10/13—interleukin 4/10/13; lnc—long non-coding RNAs (e.g., NBR2, LINC00543, RPPH1, etc.); LPS—lipopolysaccharide; M0/1/2—macrophages of phenotype 0/1/2; M1EVs—M1 macrophage-derived EVs; MET—metformin; MFHAS1—malignant fibrous histiocytoma amplified sequence 1; miR—microRNAs (e.g., miR-18a, miR-148a, miR-21-5p, miR-216b, etc.); PCSK9—proprotein convertase subtilisin/kexin type 9; PKN2—protein kinase 2; PLXDC1—plexin domain containing 1; RNASET2—ribonuclease T2; TCF4—transcription factor 4; TNF-α—tumor necrosis factor-alpha].

Figure 2

Macrophage population in homeostasis, inflammation, and cancers: the role of the SRIF system in macrophage regulation. TRMs and TAMs are both sources and targets of the SRIF system in health and disease. The impact of SST/SSAs involves preventing the production of pro-inflammatory cytokines (such as IL-1β, IL-6, TNF-α, and IFN-γ) and preventing the release of apoptosis proteins in both normal tissues and certain inflammatory conditions. In CRC, the SRIF system can both enhance macrophage cytotoxicity against cancer cells and directly inhibit tumor growth, but the mechanisms are only partially understood. [Arrows indicate positive regulation; ↑—increase; Ʇ—inhibition; ADCC—antibody-dependent cellular cytotoxicity; CRC—colorectal cancer; H₂O₂—hydrogen peroxide; IL-1β/6/12/13—interleukin 1β/6/12/13; IFN-γ—interferon-gamma; KC—Kupffer cell; Mφ—macrophage; (i)NO(S)—inducible (nitric oxide) synthase; PC—prostate cancer; SSA_s—somatostatin analogs; STT—somatostatin; SSTR_s—somatostatin receptors; SRIF—growth hormone-releasing inhibitory peptide/somatostatin; TAMs—tumor-associated macrophages; TGF-β—tumor growth factor beta; TNF-α—tumor necrosis factor-alpha; TRMs—tissue-resident macrophages].