Systemic inflammation in colorectal cancer: Underlying factors, effects, and prognostic significance

Table 1 Some systemic inflammatory markers showing altered circulating levels in colorectal cancer patients

Marker		Function	Detection method	Samples	Ref.
Acute phase proteins
CRP (C-reactive protein)	↑	Acute phase protein	ELISA	serum	Gunter et al[157]
HP (haptoglobin)	↑	Hemoglobin-binding acute phase protein	ELISA	serum	Sun et al[158]
Ferritin	↓	Protein that stores iron	meta-analysis	serum	Feng et al[159]
Cytokines and chemokines
IL6	↑	Proinflammatory cytokine	meta-analysis	serum	Xu et al[23]
IL7	↑	Cytokine involved in lymphocyte maturation	Multiplex magnetic bead assay	serum	Kantola et al[18]
IL17A	↑	Proinflammatory cytokine	meta-analysis	serum	Yan et al[160]
IL22	↑	Cytokine contributing to tissue homeostasis	meta-analysis	serum	Yan et al[160]
IL23	↑	Proinflammatory cytokine	meta-analysis	serum	Yan et al[160]
CCL2	↓	Recruitment of monocytes and macrophages	Multiplex magnetic bead assay	serum	Kantola et al[18]
CXCL5	↑	Recruitment of neutrophils	ELISA	serum	Kawamura et al[161]
CXCL8 (IL8)	↑	Recruitment of neutrophils	meta-analysis	serum	Jin et al[24]
CXCL10	↑	Recruitment of T cells and NK cells	ELISA	serum	Toiyama et el [162]
CXCL16	↑	Recruitment of T cells and NK cells	ELISA	serum	Matsushita et al[163]
SPP1 (secreted phosphoprotein 1)	↑	Leukocyte chemotaxis	streptavidin–biotin sandwich assay	serum	Werner et al[164]
Protease enzymes and their inhibitors
MMP8	↑	Protease enzyme also cleaving cytokines	immunofluorometric assay	serum	Väyrynen et al[165]
MMP9		Degradation of extracellular matrix and regulation of neutrophil action	ELISA	serum	Wilson et al[166]
TIMP1	↑	Inhibitor of metalloproteinases	meta-analysis	serum	Meng et al[167]
Growth factors and their inhibitors
ANGPTL2	↑	Growth factor contributing to the regulation of inflammation and angiogenesis	ELISA	serum	Toiyama et al[168]
ESM1	↑	Secreted angiogenic factor	ELISA	serum	Jiang et al[169]
PDGFB	↑	Proliferation of mesenchymal cells	Multiplex magnetic bead assay	serum	Kantola et al[18]
VEGFA	↑	Vascular growth factor	ELISA	serum	George et el[196]
VEGFC	↑	Vascular growth factor	ELISA	serum	Wang et al[170]
Markers of metabolism
glucose (fasting)	↑	Energy source	G6PD	serum	Ferroni et al[171]
HbA1c		Oxygen carrier	HPLC Analyzer	serum	Ferroni et al[171]
insulin (fasting)	↑	Regulator of metabolism	ELISA	serum	Ferroni et al[171]
ECM/endothelium-derived signaling proteins
Endostatin	↑	Angiogenesis inhibitor	ELISA	serum	Kantola et al[173]
POSTN (periostin)	↑	ECM protein	ELISA	serum	Ben et al[174]
VASTATIN	↑	Collagen VIII derived matrikine	ELISA	serum	Willumsen et al[172]
VCAM-1 (soluble)	↑	Multifunctional	ELISA	serum	Toiyama et el[175]
Other signaling molecules
DAND5	↑	BMP inhibitor	ELISA	serum	Miao et al[176]
LRP (leptin)	↓	Regulator of metabolism	ELISA	serum	Kumor et al[177]
Resistin	↑	Regulator of metabolism	ELISA	serum	Kumor et al[177]

ECM: Extracellular matrix; G6PD: Hexokinase/glucose-6-phosphate dehydrogenase.

Table 2 Examples of inflammatory mediators reported to be expressed by colorectal cancer cells

Inflammatory mediator	Function	Detection method	Samples	Ref.
IL6	Proinflammatory cytokine	IHC, RT-PCR	FFPE CRC specimens	Zeng et al[178]
CSF1	Proliferation, differentiation, and survival of monocytes, macrophages, and bone marrow progenitor cells; polarization of pro-tumor M2 macrophages	IHC	FFPE CRC specimens	Nebiker et al[179]
CSF2	Proliferation, differentiation, and survival of monocytes, macrophages, granulocytes and bone marrow progenitor cells, polarization of anti-tumor M1 macrophages	IHC	FFPE CRC specimens	Nebiker et al[179]
CCL2	Recruitment of monocytes and macrophages	IHC, WB	CRC cell lines, FFPE CRC specimens	Hu et al[180]
CXCL1	Recruitment of neutrophils	IHC	FFPE CRC specimens	Oladipo et al[181]
CXCL8	Recruitment of neutrophils	IHC, IF, WB	CRC cell lines, FFPE CRC specimens	Xiao et al[30]
CXCL8	Recruitment of neutrophils	IHC	FFPE CRC specimens	Oladipo et al[181]
CXCL10	Recruitment of T cells and NK cells	IHC, RT-PCR	CRC cell lines, FFPE CRC specimens	Jiang et al[182]
CXCL12	Recruitment of lymphocytes and endothelial progenitor cells	IHC	FFPE CRC specimens	Akishima-Fukasawa et al[183]
VEGFA	Angiogenesis	IHC	FFPE CRC specimens	Tuomisto et al[184]

CRC: Colorectal cancer; FFPE: Formalin-fixed paraffin-embedded; IHC: Immunohistochemistry; IF: Immunofluorescence; RT-PCR: Real-time polymerase chain reaction; WB: Western blot.

Table 3 Examples of inflammatory mediators produced by different inflammatory cells

Cell type	Inflammatory mediators	Functions	Ref.
M1 macrophage	IL6, TNF, IL12A, IL12B, IL23A, CXCL5, CXCL9, CXCL10, CXCL11,	Activation of inflammation	Murray et al[178]
M2 macrophage	IL10, CCL4, CCL13, CCL17, CCL18, MMP1, TGFB1	Resolution of inflammation	Murray et al[47]
Th1 lymphocyte	IFNG, IL2	Activation of cytotoxic immune response	Zhu et al[55]
Th2 lymphocyte	IL4, IL5, IL10, IL13	Activation of humoral immune response	Zhu et al[55]
Th17 lymphocyte	IL17A, IL17F, IL21, IL22	Activation of neutrophils	Zhu et al[55]
Treg lymphocyte	TGFB	Immunosuppression	Zhu et al[55]
Plasma cell	IL10, IL35. TNF, IL17A, CSF2	Both pro- and anti-inflammatory mediators	Dang et al[156]
Neutrophil	IL1A, IL1B, IL1RA, IL6, IL12 CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL3, CCL4, TGFB1, VEGFA	Activation of inflammation; depending on the type of polarization, also anti-inflammatory mediators are secreted	Tecchio et al[58]
Eosinophil	IL1A, IL2, IL4, IL6, IL12, CXCL1, CXCL8, CXCL10, CCL3, CCL5, CCL11	Th2 type immune responses	Davoine et al[185]
Myeloid derived suppressor cell	IL10, TGFB	Immunosuppression	Bronte et al[87]
Mast cell	IL4, IL5, IL6, TNF, CSF2	Th2 type immune responses	Amin et al[186]

Table 4 Examples of inflammatory mediators reported to be expressed by colorectal cancer associated fibroblasts

Inflammatory mediator	Function	Detection method	Samples	Ref.
IL6	Proinflammatory cytokine	IF	FFPE CRC specimens	Nagasaki et al[29]
IL6	Proinflammatory cytokine	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
IL6	Proinflammatory cytokine	ELISA	CAFs isolated from human CRC tissue	Zhang et al[187]
IL8	Proinflammatory cytokine	ELISA	CAFs isolated from human CRC tissue	Zhang et al[187]
IL11	Anti-inflammatory cytokine	qRT-PCR	CAFs isolated from human CRC tissue	Calon et al[188]
TGFB	Immunosuppression, inhibition of cytotoxic T cells and Th1 cells	IHC, WB	Cell culture (CRC cells, fibroblasts)	Hawingkels et al[68]
CXCL5	Recruitment of neutrophils	IHC, in situ hybridization	FFPE CRC specimens	Li et al[189]
CXCL8	Recruitment of neutrophils	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
CCL5	Recruitment of T cells	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
MMP1	ECM degradation	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
MMP2	ECM degradation	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
MMP3	ECM degradation	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
MMP9	ECM degradation	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
TIMP1	Inhibition of MMPs	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
TIMP1	Inhibition of MMPs	IHC, in situ hybridization	FFPE CRC specimens	Joo et al[190]
TIMP2	Inhibition of MMPs	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]
TIMP2	Inhibition of MMPs	IHC, in situ hybridization	FFPE CRC specimens	Joo et al[190]
VEGFA	Angiogenesis	LC-MS/MS	Cell culture (human cancer associated fibroblasts)	De Boeck et al[63]

CRC: Colorectal cancer; ECM: Extracellular matrix; FFPE: Formalin fixed paraffin embedded; IHC: Immunohistochemistry; IF: Immunofluorescence; LC-MS/MS: Liquid chromatography with tandem mass spectrometry; MMP: Matrix metalloproteinase; RT-PCR: Real-time polymerase chain reaction; WB: Western blot.

Table 5 Selected systemic inflammation based prognostic markers in colorectal cancer

Marker	Ref.	Study design	Study population	Outcome, HR
Acute phase proteins
CRP	Woo et al[191]	Meta-analysis, 21 studies	3934 CRC patients, stage I-II	OS, HR 2.04 (1.45–2.86); CSS, HR 4.37 (2.63–7.27); DFS, HR 1.88 (0.97–3.67)
Albumin	Gupta et al[192]	Systematic review, 12 studies	3644 CRC patients, stage I-IV	Low albumin associated with worse survival (no meta-analysis conducted)
Albumin	Ghuman et al[193]	Case-case study within a prospective cohort study (AMORIS)	4764 CRC patients, stage I-IV	OS, HR 0.57 (0.29–1.14); CSS, HR 0.36 (0.16–0.85)
mGPS	Lu et al[194]	Meta-analysis, 41 studies	9839 CRC patients, stage I-IV	OS, HR 2.20 (1.88–2.57); CSS, HR 1.86 (1.59–2.17)
HP (haptoglobin)	Ghuman et al[193]	Case-case study within a prospective cohort study (AMORIS)	4764 CRC patients, stage I-IV	OS, HR 1.28 (1.08–1.51); CSS, HR 1.17 (0.95–1.45)
Blood cell count parameters
Neutrophil-to-lymphocyte ratio	Li et al[148]	Meta-analysis, 16 studies	5897 CRC patients, stage I-IV	OS, HR 1.66 (1.36–2.02); CSS, HR 2.27 (1.75–2.96); DFS, HR 1.54, (1.18–2.02)
Lymphocyte-to-monocyte ratio	Tan et al[149]	Meta-analysis, 15 studies	11783 CRC patients, stage I-IV	OS, HR 0.57 (0.52-0.62); CSS, HR 0.55 (0.32-0.95); DFS, HR 0.77 (0.70-0.84)
Platelet count	Rao et al[152]	Meta-analysis, 9 studies	3413 CRC patients, stage I-IV	OS, HR 2.11 (1.68-2.65); DFS, HR 2.51 (1.84-3.43)
Platelet-to-lymphocyte ratio	Tan et al[153]	Meta-analysis, 15 studies	3991 CRC patients, stage I-IV	OS, HR 1.53 (1.24–1.89), DFS, HR 1.68 (1.07–2.62)
Anemia	Wilson et al[150]	Meta-analysis, 12 studies	3588 CRC patients, stage I-IV	OS, HR 1.56 (1.30-1.88), DFS, HR 1.34 (1.11-1.61)
Cytokines, chemokines, and their receptors
IL6	Xu et al[23]	Meta-analysis, 10 studies	860 CRC patients, stage I-IV	OS, HR 1.76 (1.42–2.19); DFS, HR 2.97 (1.76–5.01)
TNFRSF11B (Osteoprotegerin)	Birgisson et al[20]	Prospective cohort study	261 stage II-IV CRC patients	OS, HR 3.33
Protease enzymes and their inhibitors
TIMP1	Lee et al[195]	Meta-analysis, 10 studies	1477 CRC patients, stage I-IV	OS, HR 2.25 (1.56-3.25)

CRC: Colorectal cancer; CSS: Cancer-specific survival; DFS: Disease-free survival; HR: Hazard ratio; OS: Overall survival.