The regulatory network of the chemokine CCL5 in colorectal cancer

Figures & data

Figure 1. Receptors related of the chemokine CCL5. In addition to the cognate receptor CCR5, specific receptors include CCR1, CCR3 and CCR4. Noncanonical receptors include ACKR1, ACKR2, CCRL2 and CD44.

Table 1. Function of the CCL5 receptor.

Receptor	Function
CCR1	Highly expressed in human monocyte/macrophage [33] contribute to transendothelial migration of monocytes and T cells in atherogenic lesions and then promote disease progression [34] monocyte recruitment, not involved in apoptosis [35]
CCR3	Highly expressed in human eosinophils, basophils and mast cells [36,37] correlate with allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis. And as a possible pathogenic mechanism of such diseases [38,39] tumor progression [40]
CCR4	Highly expressed in human T lymphocyte cells [41] play a central role in T cell migration to the thymus, and T cell maturation and education [42] correlate with leukemia and lymphoma, contributing to tumor survival [43] correlate with autoimmune disease such as multiple sclerosis, Primary Sjögren’s syndrome, asthma and atopic dermatitis and then promote disease progression [17,39,44, 45]
CCR5	Contribute to transendothelial migration of monocytes and T cells in atherogenic lesions [34] cancer progression: ①DNA damage repair [46] ②extracellular matrix remodelling [47,48] ③tumour progression and metastasis [49] ④cancer stem cell proliferation [50] ⑤autocrine/paracrine signalling [51] ⑥tumor angiogenesis [52] ⑦metabolic reprogramming [53] ⑧immunosuppression [54]

Table 2. Expression of CCL5 in human cells and its role.

Receptor	Cell type^a	Mechanisms^b	Disease	Ref.
	Microglia	Neuroinflammation (mTOR signaling)	Autism Spectrum Disorder	[55]
	Macrophages	Tumor progression and chemoresistance (inhibiting apoptosis)	Cholangiocarcinoma	[56]
	Macrophages	Immune escape (p65/STAT3-CSN5-PD-L1 pathway)	colorectal cancer	[57]
	Tumour tissues	Regulating the tumour immune microenvironment(CD8^+ T cell infiltration)	colorectal neuroendocrine carcinoma	[58]
	Tumour tissues	Mast cell recruitment tumor progression	clear cell renal cell carcinoma	[59]
	Platelet	Thromboinflammatory responses(leukocyte chemoattraction and monocyte recruitment)	Essential Thrombocythemia	[60]
CCR1	Mesenchymal stem cells	Epithelial–mesenchymal transition and progression(CCL5/β-catenin/Slug pathway)	colorectal cancer	[61]
CCR1	White adipose tissue	Antiapoptotic (Erk/Akt pathways) macrophage recruitment	Obesity	[62]
CCR3	Stromal cells	Tumor progression	Breast Cancer	[40]
CCR1 CCR3	Platelets Endothelium	Leukocyte recruitment	Atherosclerosis	[63]
CCR1 CCR3	Ovarian cancer stem-like cells	Tumor metastatic(CCL5/CCR1-CCR3/NF-KB/MMP-9)	ovarian cancer	[64]
CCR4	CCR9^+effector CD8^+ T cells	Autoimmune damage	Primary Sjögren’s syndrome	[17,65]
CCR1 CCR5	Cancer cell	Recruits blood monocytes	Diffuse large B-cell lymphoma	[66]
CCR1 CCR5	Cancer cell	Development and metastasis of Breast Cancer(macrophage recruitment)	Breast Cancer	[67]
CCR3 CCR5	Brain microvascular endothelial cells	Zika virus pathogenesis and spread(CCL5/CCR3-CCR5/ERK1/2)	Microcephaly	[18]
CCR5	Colorectal cancer cell	Tumor progression (apoptosis of CD8 T cells, infiltration of Treg cells)	colorectal cancer	[50]
CCR5	Pancreatic cancer cells	Immunosuppression (recruit FOXP3^+ Treg cells)	pancreatic ductal adenocarcinoma	[54,68]
CCR5	Glioblastoma Cells	Proliferation and invasion(Remodeling the tumor microenvironment)	Glioblastoma Cells	[48]
CCR5	Cancer cell	Acquired resistance to trastuzumab(ERK)	Breast Cancer	[31]
CCR5	Cutaneous neurofibromas cells	Nerve injury(macrophage recruitment YAP)	neurofibromatosis type 1(Cutaneous neurofibromas)	[69]
CCR5	Macrophages	Chemo-resistance and distant metastasis(STAT3-associated signaling)	prostatic cancer	[20,70]

For the first 6 rows, there are no receptors specified because the relevant receptors are not specified in these six literatures.

^aTypes of cells secreting CCL5.

^bSpecific mechanisms of CCL5 receptor cells and downstream activated pathways.

Figure 2. CCL5 promotes tumor progression by recruiting immunosuppressive cells. Mast cells recruited by CCL5 promote tumor neovascularization by secreting the cytokine TNF- α and activating the PI3K/AKT/GSK3 β/AM pathway; mast cells inhibit the activity of CD8+ T cells by secreting the cytokines IL-10 and TGF-β, and play immunosuppressive roles; mast cells and tumor-associated macrophages can directly promote tumor metastasis by secreting MMP-9. Tumor-associated macrophages are recruited by CCL5 to promote tumor neovascularization via the secretion VEGF; and TAMs directly inhibit the activity of CD8+ T cells.

Figure 3. All kinds of cells in tumor microenvironment promote tumor progression in different ways: TAMs inhibit the activity of CD8+ T cells through CCL5/Kappa p65/STAT3 signaling pathway. Colorectal cancer cells recruit Treg cells to inhibit CD8⁺ T cell activity by secreting CCL5, or act on Flibroblasts by secreting CCL5. Flibroblasts promote tumor angiogenesis by secreting VEGF, synthesizing and secreting collagen protein, and activating SLC25A24 and Akt/pmTOR signaling pathways. Mesenchymal stem cells and dendritic cells promote stromal epithelial transformation by secreting CCL5.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.