Chinese Medicine for the treatment of pancreatic cancer by targeting the tumor microenvironment: mechanistic insights and therapeutic potential

Figures (2) Tables (2)

Figure 1.
Components of the TME in PDAC. Heterogenous CAFs and PSCs produce materials for ECM formation and contribute to desmoplasia. The immune cells infiltrated into tumors include TAMs, TANs, MDSCs, Treg cells, cytotoxic T cells, B cells, NK cells, and so on, creating an immunosuppressive environment. Microbiota, neurons, and vasculature also serve as important constituents of the TME in PDAC.
Figure 2.
Effects and mechanisms of CHM in targeting TME components. CHM inhibits the proliferation and activity of PSCs and CAFs, as well as remodeling of the ECM, via suppression of a variety of fibrotic mediators, miRNAs, and pathways such as TGF-β/Smad. Vasculature in the TME can be regulated by CHM mainly through inhibition of NF-κB-mediated VEGF, VEGF binding to VEGFR2, pathways including STAT3 and TGF-β/Smad, and modulation of miRNAs. Multiple tumor-infiltrating immune cells have been revealed as targets of CHM, including targeting the polarization of M1/M2 macrophages, inhibition of TAMs, MDSCs, TANs, and Treg infiltration, as well as increasing cytotoxic T cell and NK cell responses, involving cytokines and chemokines such as IL-6, ARG1, MRC1, TGF-β, and signaling pathways including STAT6 and PI3K/AKT/mTOR.

Target	CHM formula/extract/compound	Constituents/solvent/origins	Model	Effect	TME-modulatory mechanisms	Ref.
PSCs	Phoenix Dactylifera L.	Water, EtOH, acetone, EtOAc extracts	PSCs	↓ PSCs’ fibrotic phenotype	↓ FN1, α-SMA ↑ antioxidant capacity	[76]
	Resveratrol	Multiple	PSCs PANC-1 cells	↓ PSCs activation, migration, invasion ↓ ROS-induced glycolysis in PSCs	↓ α-SMA ↓ ROS/miR-21 ↑ PTEN	[78]
	Resveratrol	Multiple	PSCs PANC-1, Mia Paca-2 cells KPC mice	↓ PSCs activation	↓ HIF-1α, α-SMA, SDF-1, IL-6	[77]
	Trans-resveratol	Multiple	LTC-14 cells	↓ PSCs ↓ Fibrotic mediators	↓ α-SMA, FN1 ↓ Acta2, Fn1, Col2-α1 ↓ p-AKT ↓ NF-κB and AKT signaling	[79]
CAFs	Qing-Yi-Hua-Ji formula	Scutellariae Barbatae Herba, Hedyoti Diffusae Herba, Amorphopallus Ribieri Rhizoma, Coicis Semen, Gynostemmatis Pentaphylli Herba, Ganoderma, Amomi Rotundus Fructus	Panc02 cells C57 mice	↓ CAFs proliferative activity	↓ SDF-1, α-SMA, vimentin	[80]
	α-Mangostin	Mangosteen	NIH3T3 PANC-1, PANC-1-Luc2 cells BALB/c nude mice	↓ CAFs ↑ Vascular normalization	↓ α-SMA, FAP-α, FN ↓ TGF-β, p-Smad2, p-Smad3 ↓ TGF-β/Smad signaling	[91]
	Curcumin	Curcumae Longae Rhizoma	CAFs Capan-1, PANC-1 cells, BALB/c nude mice	↓ CAFs ↓ Mesenchymal characteristic	↓ Vimentin, α-SMA	[82]
	Quercetin	Multiple	NIH3T3 cells Panc02, Panc02-luc cells C57BL/6 mice	↓ CAFs ↑ Blood perfusion	↓ α-SMA, Wnt 16 ↓ HIF-1α, FN, collagen	[83]
ECM	Huachansu	Bufonis Venenum	PSCs SW1990 cells BALB/c-nu mice	↓ ECM	↓ collagen-1 ↑ Smad4 ↓ Smad2/3, p-Smad2/3 ↓ TGF-β/Smad2/3 pathway	[84]
Vasculature	Dahuang Zhechong pill	Rhei Radix et Rhizoma, Eupolyphaga seu Steleophaga, Armeniacae Amarum Semen, Persicae Semen, Scutellariae Radix, Rehmanniae Radix, Paeoniae Alba Radix, Glycyrrhizae Radix, Tabanus, Hirudo, Holotrichia Sauteri Moser, Toxicodendri Resina	CFPAC-1 cells Nude mice	↓ Angiogenesis	↓ VEGF, NF-κB	[85]
	Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang	Radix Angelicae Sinensis, Cinnamomi Cortex, Paeoniae Alba Radix, Clematidis Armandii Caulis, Asari Radix et Rhizoma, Glycyrrhizae Radix, Jujubae Fructus, Evodiae Fructus, Zingiberis Rhizoma Recens	HUVECs Panc-28-luc cells BALB/c nude mice	↓ HUVECs/HDMECs migration, invasion, and tube formation ↓ Vascular leakage	↓ Phosphorylation of VEGFR2, FAK, SRC, AKT, IKKα/β, IκBα, NF-κB ↓ MMP-9 ↓ VEGF binding to VEGFR2	[86]
	Sauchinone	Saururi Herba	PANC-1, BxPC-3 cells	↓ Tumor blood flow	↓ VEGF, HIF-1α	[87]
	Oxymatrine	Sophorae Flavescentis Radix	PANC-1 cells BALB/C (nu/nu) mice	↓ Angiogenesis	↓ NF-κB-mediated VEGF	[88]
	Ursolic acid	Multiple	AsPC-1, MIA PaCa-2, Panc-28 cells Athymic nu/nu mice	↓ Angiogenesis	↓ VEGF, VEGFR2, CD31 ↓ p-STAT3 ↓ STAT3 signaling	[89]
	Emodin	Multiple	SW1990 cells BALB/c nu/nu mice	↓ Angiogenesis	↑ TβRI, TβRII, Smad4 ↓ TGF-βI, Angptl4 ↑ miR-20b ↓ miR-155 and miR-210	[90]
TAMs	Qingyihuaji formula	Scutellariae Barbatae Herba, Hedyoti Diffusae Herba, Amorphopallus Ribieri Rhizoma, Coicis Semen, Gynostemmatis Pentaphylli Herba, Ganoderma, Amomi Rotundus Fructus	BxPC, SW1990 cells BALB/c-nu/nu nude mice	↓ TAMs	↓ IL-6	[91]
TAMs	Qingyihuaji formula		Panc02 cells C57 mice	↓ TAMs	↓ CCL5	[80]
	Xihuang pill	Bovis Calculus, Moschus, Olibanum, Myrrha	RAW 264.7 cells Panc02, Panc02-luc cells C57BL/6J mice	↑ M1-TAMs ↓ M2-TAMs	↑ CXCL9, CXCL10, Cd86 ↓ Cd206 ↓ Kyn-AhR axis ↓ AKT/mTOR pathway	[92]
	Modified Sijunzi decoction	Poria, Codonopsis Radix, Rhodiolae Crenulatae Radix et Rhizoma Atractylodis, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma, Dioscoreae Rhizoma	Panc02 cells C57BL/6 mice	↑ M1-TAMs ↓ M2-TAMs	↓ ARG1, IL-10, IL-6, PPARγ	[93]
	Osthole	Cnidii Fructus	RAW 264.7 Panc02 cells C57BL/6 mice	↓ M2-TAMs infiltration ↓M2 polarization	↓ MRC1, CCL22, TGF-β ↓ p-ERK1/2, p-STAT6 ↓ STAT6 and C/EBP β signaling:	[94]
	Icarrin	Epimedii Herba	RAW 264.7 Panc02 cells C57BL/6 mice	↓ M2-TAMs infiltration ↓ M2 polarization	↓ ARG1, MRC1 ↓ p-STAT6 ↓ STAT6 signaling	[95]
	Isobavachalcone	Fructus Psoraleae	RAW 264.7 Panc02 cells C57BL/6 mice	↓ M2-TAMs infiltration ↓ M2 polarization	↓ ARG1, MRC1	[96]
	Saikosaponin D	Bupleuri Radix	RAW 264.7, H7, BMDM Panc02 cells C57BL/6 mice	↑ M1-TAMs ↓ M2-TAMs	↓ STAT6 and PI3K/AKT/mTOR in RAW264.7 cells	[97]
TANs	Piji pills	Curcuma Rhizoma, Sparganii Rhizoma, Alpiniae Officinarum Rhizoma, Pericarpium Citri Reticulatae Viride, Aucklandiae Radix, Gleditsiae Abnormalis Fructus, Pulvis Fumi Carbonisatus	HL-60 cells SW1990 BALB/c nude mice	↓ NETs	↑ CD45, F4/80, Ly6G/Ly6C, IL-8 ↓ NE, MPO, CitH3	[98]
MDSCs	Icarrin	Epimedii Herba	RAW 264.7 cells Panc02 cells C57BL/6 mice	↓ PMN-MDSCs		[95]
	Isobavachalcone	Fructus Psoraleae	RAW 264.7 cells Panc02 cells C57BL/6 mice	↓ MDSCs	↓ ARG, TGFβ	[96]
	Saikosaponin D	Bupleuri Radix	H7, RAW 264.7, BMDM cells Panc02 cells C57BL/6 mice	↓ PMN-MDSCs		[97]
T cells	Juzen-Taiboto	Codonopsis Radix, Atractylodis Rhizoma Alba, Rhizoma Poria, Glycyrrhizae Radix et Rhizoma, Rehmanniae Radix Preparata, Paeoniae Radix Alba, Chuanxiong Rhizoma, Angelicae Sinensis Radix, Astragali Radix, and Cinnamomi Cortex	Clinical trial	↑ CD4/CD8 cells ↓ Treg cells		[99]
	Modified Sijunzi decoction	Poria, Codonopsis Radix, Rhodiolae Crenulatae Radix et Rhizoma Atractylodis, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma, Dioscoreae Rhizoma	Panc02 cells C57BL/6 mice	↑ CD8⁺ T cells	↑ L-arginine	[93]
	Isobavachalcone	Fructus Psoraleae	RAW 264.7 cells Panc02 cells C57BL/6 mice	↑ CD8⁺T cells		[96]
	Saikosaponin D	Bupleuri Radix	H7, RAW 264.7, BMDM cells Panc02 cells C57BL/6 mice	↑ CD3⁺CD8⁺ cells		[97]
NK cells	Juzen-Taiboto	Codonopsis Radix, Atractylodis Rhizoma Alba, Rhizoma Poria, Glycyrrhizae Radix et Rhizoma, Rehmanniae Radix Preparata, Paeoniae Radix Alba, Chuanxiong Rhizoma, Angelicae Sinensis Radix, Astragali Radix, and Cinnamomi Cortex	Clinical trial	↑ NK cells		[99]
	Saikosaponin D	Bupleuri Radix	H7, RAW 264.7, BMDM cells Panc02 cells C57BL/6 mice	↑ NK cells		[97]
ARG1: Arginase-1; BMDM: Bone marrow mononuclear cells; CAFs: Cancer-associated fibroblasts; ECM: Extracellular matrix; FN: Fibronectin; Glut1: Glucose transporter 1; HDMECs: Human dermal microvascular endothelial cells; HIF: Hypoxia-Inducible Factors; HUVECs: Human umbilical vein endothelial cells; IL: Interleukin; MDSCs: Myeloid-derived suppressor cells; NETs: Neutrophil extracellular traps; NK: Natural killer; PMN-MDSCs: Polymorphonuclear myeloid-derived suppressor cells; PSCs: Pancreatic stellate cells; ROS: Reactive oxygen species; TAMs: Tumor-associated macrophages; TANs:Tumor-associated neutrophils; TGF-β: Transforming growth factor-β; Treg: Regulatory T. α-SMA: Alpha-smooth muscle actin; ↓: Decreased level; ↑: Elevated level.

Table 1.

TME-modulatory effects and corresponding mechanisms of CHM formulae, herbs and active compounds.

CHM formulae/extract/ compounds	Target	Constituents/solvent/ origins	Toxicity
Qingyihuaji formula	CAFs, TAMs, vasculature	Amorphopallus Ribieri Rhizoma	Toxic
Dahuang Zhechong pill	Vasculature	Toxicodendri Resina	Slight
		Armeniacae Amarum Semen	Toxic
		Holotrichia Sauteri Moser	Extreme
		Hirudo	Slight
		Persicae Semen	Slight
Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang	Vasculature	Evodiae Fructus	Slight
Extreme: Causing severe adverse response at low dosage. Toxic: Therapeutic dose being close to toxic dose. Slight: Toxic when used in excess.

Table 2.

Toxicity of selected CHM.