Table 1 Previously identified stromal cell subpopulations in individual studies.
From: Rebuilding the microenvironment of primary tumors in humans: a focus on stroma
Stromal cell | Cancer type | Subpopulation | Markers | Feature | Ref |
|---|---|---|---|---|---|
CAF | Breast cancer | CAF-S1 | CD29Med FAPHi FSP1Low-Hi αSMAHi PDGFRbMed-Hi CAV1Low | - High expression of CCL11, CXCL12, 13, 14 - Myofibroblastic subset - Enriched in TNBC - Immunosuppressive - Increase T lymphocyte survival and differentiation - Associated with accumulation of FOXP3 + T lymphocytes - Correlated with CD45+ hematopoietic cells and macrophages - Anti-correlated with CD8 + T lymphocytes - Enhance Treg capacity to inhibit effector T cells | |
CAF-S2 | CD29Low FAPNeg FSP1Neg-Low αSMANeg PDGFRbNeg CAV1Neg | - Enriched in LumA BC | |||
CAF-S3 | CD29Med FAPNeg FSP1Med-Hi αSMANeg-Low PDGFRbMed CAV1Neg-Low | - Associated with Juxta-tumor | |||
CAF-S4 | CD29Hi FAPNeg FSP1Low-Med αSMAHi PDGFRbLow-Med CAV1Neg-Low | - Enriched in TNBC and HER2 BC - Myofibroblastic subset - Associated with CD8 + T lymphocytes - Anti-correlated with FOXP3 + T lymphocyte | |||
Breast cancer | CAF-S1 ECM-myCAF | GJB2, LRRC15 | - ECM-myofibroblastic CAF - Enriched in LumA BC - Involved in collagen synthesis and ECM organization | ||
CAF-S1 Detox-iCAF | ADH1B, GPX3 | - Detoxification-inflammatory CAF - Enriched in TNBC - Involved in detoxification and inflammatory response | |||
CAF-S1 IL-iCAF | RGMA, SCARA5 | - Response to stimuli - Enriched in TNBC - Involved in the response to growth factor, TNF signaling, and IL pathway | |||
CAF-S1 TGFβ-myCAF | CST1, TGFB1 | - TGFβ-myofibroblastic CAF - Enriched in LumA BC - Involved in response to TGFβ stimulus and matrisome | |||
CAF-S1 Wound-myCAF | SEMA3C, SFRP4 | - Wound healing-myofibroblastic CAF - Enriched in LumA BC - Involved in the assembly of collagen fibrils and wound healing - Correspond to apCAF | |||
CAF-S1 IFNγ-iCAF | CCL19, CCL5 | - IFNγ and cytokines | |||
CAF-S1 IFNαβ-iCAF | IFIT3, IRF7 | - IFNαβ-inflammatory CAF | |||
CAF-S1 Acto-myCAF | GGH, PLP2 | - Actomyosin-myofibroblastic CAF | |||
CAF-S2 | FAPNeg CD29Low SMANeg | - Abundant in healthy tissue | |||
CAF-S3 | FAPNeg CD29Med SMANeg | - Abundant in healthy tissue | |||
CAF-S4 | FAPNeg SMAHi CD29Hi MCAMHi | - Restricted to cancer and metastatic lymph nodes - Characterized by a perivascular signature - Pro-metastatic function - Contractile | |||
Breast cancer | vCAF | Rgs5 | - Vascular CAF - Upregulated vascular development and angiogenesis genes - Enriched in tumor core - Localized in proximity to vasculature | ||
mCAF | Pdgfra, Mfap5, Dcn | - Matrix CAF - Strong ECM signature - Upregulated ECM, matrisome, and EMT associated genes - Low abundance in the tumor core | |||
cCAF | Nuf2, Mki67 | - Cycling CAF - Upregulated cell-cycle-related genes - Proliferative segments of vCAF | |||
dCAF | Scrg1, Sox9, Sox10 | - Developmental CAF - Upregulated development and morphogenesis of tissue-associated genes - Originate from tumor cells that have undergone EMT | |||
PDAC | myCAF | ACTA2, TAGLN, MMP11, MYL9, HOPX, POSTN, TPM1, TPM2, ACTA2high | - Myofibroblastic CAF - Adjacent to cancer cells - Associated with smooth muscle contraction, focal adhesion, ECM organization, and collagen formation | ||
iCAF | IL6, PDGFRA, CXCL12, CFD, DPT, LMNA, AGTR1, HAS1, CXCL1, CXCL2, CCL2, IL8, ACTA2low Ly6Chigh | - Inflammatory CAF - High inflammatory mediators: IL6, IL11, LIF - Located in the desmoplastic areas of the tumor - Distant from cancer cells - Associated with the synthesis of hyaluronan and the complement pathway | |||
apCAF | H2-Ab1, Cd74, Saa3, Slpi | - Antigen-presenting CAF - Express MHC class II-related genes - Induce TCR ligation in CD4 + T cells in an antigen-dependent manner | |||
Lung cancer | Cluster 1 | COL10A1 | - Highly enriched in tumor - EMT-related signal - ECM phenotype - HOXB2 and FOXO1 are highly upregulated | ||
Cluster 2 | COL4A1 | - The highest expression of ACTA2, a myofibroblast marker - Involved in myogenesis, NOTCH pathway, and angiogenesis - Myogenesis phenotype | |||
Cluster 4 | PLA2G2A | - Similar to Cluster 1 - COL14A1high | |||
Cluster 5 | MMP3 | - Low expression of myogenesis signature - High expression of mTOR signature and glycolysis genes | |||
Cluster 6 | FIGF | - Nonmalignant fibroblast - High expression of elastin - Low expression of some collagens: collagen type I, III, V, and VIII | |||
Cluster 7 | CCL2 | - Present in NSCLC patients - Similar to Cluster 5 but with low expression of glycolysis genes | |||
Gastric cancer | myCAF | TPM1, TPM2, MYL9, TAGLN, POSTN | - Myofibroblastic CAF - Prevalent in intestinal-type GC - Negatively correlated with tumor stemness | ||
iCAF | IL6, IL11, IL24, CXCL1, CXCL2, CXCL5, CXCL6, MMP1, MMP3, MMP10 | - Inflammatory CAF - Prevalent in diffuse-type GC - Associated with GC invasion - Promote stemness of tumor cells, high stemness score | |||
inCAF | PDGFRA, POSTN, ID1, ID3 | - Intermediate CAF - Negatively correlated with tumor stemness - inCAF signal is increased with tumor progression from the premalignant state | |||
Colorectal cancer | CAF-A | FAP, MMP2, LUM, COL1A2 | - Involved in ECM remodeling - Intermediate state between NMFs and CAF-B | ||
CAF-B | ACTA2, TAGLN, PDGFA | - Express cytoskeletal genes known for activated myofibroblast markers | |||
NMFs | SFRP1/2, MFAP5, DPT, S100A4 | - Normal mucosa fibroblasts | |||
Pancancer | myoCAF | ACTA2, MYH11 | - Myofibroblastic CAF - Enriched tumorigenesis and myogenic regulons (TBX2, MEF2C each) | ||
inflaCAF | MMP11, CTHRC1, FAP, TGFB1 | - Inflammatory CAF - Associated with dedifferentiation regulon | |||
adiCAF | CFD | - Adipogenic CAF - Associated with EMT regulon | |||
EndMT-CAF | RGS5, ACTA2, PLVAP, VWF | - Endothelial to Mesenchymal Transition CAF - Associated with angiogenesis and endothelial differentiation | |||
PN-CAF | MPZ, S100B, LGI4, PLP1 | - Peripheral nerve-like CAF | |||
apCAF | ACTA2, HLA-DRA, CD74, HLA-DRB1 | - Antigen-presenting CAF - Enriched in PDAC - Interaction with tumor-infiltrating T-cell clusters | |||
TAM | Breast cancer | Stromal Macrophage | CD11b + MRC1+ | - Harbor potent T-cell activation capacity | |
Hyperplastic Ductal Macrophage | CD11b- | - Associated with an advanced tumor stage - Potent phagocytes - Not efficient for activating CD8 T cells - Locally accumulated through the active proliferation | |||
Malignant ductal TAM | CD11b + SPP1+ | - Associated with poor prognosis - Regulate immunosuppressive functions of TAMs of monocytic origin | |||
Breast cancer | LAM1:FABP5 TAM | SPP1, FABP5 | - Similar to lipid-associated macrophages (LAM) - High expression of TREM2 and lipid/fatty acid metabolic genes - Reduced proportion in HER2 + BC - Correlation with worse survival | ||
LAM2:APOE TAM | APOE | - Similar to lipid-associated macrophages - High expression of TREM2 and lipid/fatty acid metabolic genes | |||
CXCL10 TAM | CXCL10, CXCL11 | - M1-like phenotype | |||
EGR1, SIGLEC1 TAM | IL2RA, CD209 | - M2-like phenotype | |||
Gastric cancer | HSP + TAM | HSPA6, HSPA1B, HSPB1 | - Increased HSP-associated genes | ||
THBS1 + TAM | THBS1 | - N/A | |||
Chemokine-TAM | CCL3, CCL18, CCL20 | - Increased expression of chemokines | |||
MMP-TAM | MMP9, MMP12 | - MMP genes | |||
Complement-TAM | C1QA, C1QB, C1QC | - Complement family | |||
Cell cycle-TAM | TOP2A, STMN1 | - Cell-cycle regulation genes | |||
Colon cancer | C1QC + TAM | C1Q genes, TREM2, MERTK, CD80 | - Derived from IL1B+ Tissue-resident macrophage (TRM) - Expression of MAF/MAFB and JUN/FOS - Increased inflammatory signatures, including complement activation, antigen processing, and presentation pathways | ||
SPP1 + TAM | SPP1, MARCO, VEGFA | - Derived from NLRP3 + TRM - Expression of the level of HLA-DRs, CEBPB, and ZEB2 - Angiogenic signatures: enriched tumor angiogenesis, ECM receptor interaction, and tumor vasculature pathways | |||
Colorectal cancer | C1QC + MRC1- TAM | C1QC | - Closely related to CD14/CD16 monocytes in blood | ||
SPP1 + TAM | C1QC, MRC1, STAT1, PPARG | - Tumor-specific filtration - Originated from THBS1 + TAM - Exhibit shorter progression-free survival | |||
THBS1 + TAM | THBS1 | - Promote malignant migration of cancer - Capable of performing antigen processing and presentation and regulating intestinal immune network for IgA production - Can differentiate into SPP1+ macrophages | |||
VCAN + TAM | VCAN | - N/A | |||
Colorectal cancer | Proinflammatory macrophage | IL1B, IL6, S100A8, S100A9 | - Upregulation of genes associated with cytokines | ||
SPP1+ macrophage A | SPP1, IL6 | - Enriched in tumor core and border - Proinflammatory phenotype - Association with CMS type 4 | |||
SPP1+ macrophage B | SPP1, CD163, SEPP1, APOE, MAF | - Enriched in tumor core and border - Anti-inflammatory phenotype | |||
Proliferating macrophage | MKI67, KIAA0101 | - Upregulation of genes associated with cell cycle | |||
Hepatocellular carcinoma | TAM1 | FOLR2, CD163, C1QB, SEPP1, CD163high CD206high | - Fetal-like TAM - FOLR2 expressing TAM - Exhibit immunosuppressive interactions - Higher expression of immunomodulatory chemokines - Enrichment with TIGIT+ cells | ||
TAM2 | SPP1, TREM2, FABP5, NUPR1, CD163low CD206low | - SPP1 + TAM | |||
TAM3 | MT1G, MT2A, MT1X, CD163low CD206low | - MT1G-enriched TAM | |||
Pancancer | C1QC + TAM | C1QC | - Tumor enriched macrophage - Higher M2 signature and phagocytosis scores | ||
SPP1 + TAM | SPP1 | - Tumor enriched macrophage - Higher M2 signature and angiogenesis signature | |||
ISG15 + TAM | ISG15 | - Tumor-enriched macrophage - Upregulated IFN inducible genes - Higher expression of canonical M1 signature | |||
FN1 + TAM | FN1 | - Tumor-enriched macrophage - Mainly present in kidney cancer - Proangiogenic TAM | |||
INHBA + TAM | INHBA | - Compensate SPP1 + TAM in stomach cancer with a proangiogenic signature | |||
VCAN + TAM | VCAN | - Compensate SPP1 + TAM in BC with a proangiogenic signature | |||
LYVE1 Macrophage | LYVE1 | - Identified within multiple cancer types - Enriched in noncancer tissue - Tissue-resident interstitial macrophage | |||
NLRP3 Macrophage | NLRP3 | - Enriched in noncancer tissue - Represent proinflammatory TRM (Tissue-resident macrophage) | |||
Pancancer | HES1 + TAM | C1QA, C1QB, C1QC, IGF1, CCL3, CCL4 | - Harbor an embryonic signature | ||
TREM2 + TAM | APOC1, APOE, SPP1, FABP5 | - Accumulated only in tumor tissue - Involved in metabolic disorders - Potentially immunosuppressive role | |||
IL4I1 + TAM | IL4I1 + PD-L1 + IDO1+ CD38, IDO1, CXCL9, CXCL10, CXCL11 | - Antigen presentation, interaction with both Th2 and Th1 T cells, T-cell exhaustion, and tryptophan degradation - Suppress T cells and attract Tregs into the tumor by producing chemokine, expressing PD-L1 and PD-L2, and degrading IL4I1/AHR tryptophan - Exhibit immunosuppressive - Promote the entry of Treg into the tumor | |||
Proliferating TAM | TOP2A, MKI67, IDO1 | - Accumulated in all cancer types | |||
TEC | PDAC | Endothelial 1 | IGFBP3, SPP1, CFH, IGLL5, TIMP1 | - Higher expression of HIF1A - Enriched for ECM organization, regulation of vasculature development, regulation of angiogenesis, cell junction assembly and epithelial cell migration | |
Endothelial 2 | CLPS, PRSS1, CTRB1, CA4, CELA3A | - Represent normal pancreatic tissue | |||
Lung cancer | Cluster1 | MT2A | - Normal EC | ||
Cluster 3 | IGFBP3 | - Tumor EC - Enrichment of Myc target, nucleotide metabolism, OXPHOS-associated genes - Immune activation-associated genes are downregulated | |||
Cluster 4 | SPRY1 | - Tumor EC - Enrichment of Myc target, nucleotide metabolism, OXPHOS-associated genes - Immune activation-associated genes are downregulated | |||
Cluster 5 | EDNRB | - Normal EC | |||
Cluster 6 | PDPN, PROX1 | - Lymphatic EC | |||
Gastric cancer | E0 | IGFBP5, STC1, IGFBP3 | - Influence angiogenic sprouting - Upregulation of mTOR and IGF-1 signaling - Increase the invasion and migration of tumor cells | ||
E1 | FOXO1, FOXP1, JUN | - Associated with the regulation of T-cell exhaustion signaling pathway - Suppress immune response | |||
E2 | N/A | - Low activity - Normal endothelial cells | |||
E3 | NRP1, FGFR1 | - VEGF receptor encoding genes are significantly upregulated - White adipose tissue browning pathway and STAT3 pathways are activated - Promote cancer cell invasion and angiogenesis | |||
Gastric cancer | Endo1 | COL4A1, COL4A2, PROS1 | - Predominantly enriched in tumor - Downregulated MHC class II genes - Limited antigen presentation function - Strong activation of TNF, VEGF, PDGF, PGF, and Notch signaling - Involved in angiogenesis | ||
Endo2, Endo3, Endo4 | N/A | - N/A | |||
Colorectal cancer | Tip-like EC | RGCC, RAMP3 | - Overrepresentation of regulators of angiogenesis in tumor - Overrepresentation of antigen processing and presentation in normal | ||
Stalk-like EC | ACKR1, SELP | - Associated with apoptosis inhibition and proliferation | |||
Proliferative EC | BIRC5, CKS1B | - Overexpression of BIRC5 and CKS1B | |||
Lymphatic EC | LYVE, PROX1 | - Found both in normal and tumor | |||
Hepatocellular carcinoma | PLPP3 + TEC | PLPP3 | - Enriched in tumor tissue | ||
PLVAP + TEC | PLVAP, HLA-DRA, | - Enriched in tumor tissue - Facilitate the emergence of fetal-like macrophages - Mainly enriched in fetal and tumor tissues - Major subset expressing the receptor for VEGF | |||
IGFBP3 + TEC | IGFBP3 | - Enriched in tumor tissue | |||
Clear cell renal cell carcinoma | AVR1 TEC | PLVAP, FLT1, KDR, FLT4, EDNRB, VWF, HSPG2 | - Higher expression of VEGF receptor - Upregulation of genes involved in hemostasis, angiogenesis, and stimulation of endothelial growth and regeneration | ||
AVR2 TEC | ACKR1, SELP | - Evade angiogenesis inhibitors | |||
Glioblastoma | Pe1 EC | KLF2, TIMP3, SLC2A1, SLCO1A2, TSC22D1, DEGS2, CAVIN2 | - Quiescent endothelial cells derived from nonmalignant tissue - Associated with vascular integrity and BBB function | ||
Co1 EC | COL4A1, COL4A2, HSPG2, INSR, KDR | - Derived from tumor core - Angiogenic phenotype - Associated with developmental and tumor angiogenesis, vascular basement membrane remodeling, cytoskeletal rearrangements, angiogenic sprouting, and endothelial tip cell formation | |||
Co2 EC | TMSB4X, RPLP2, RPL39, GAPDH, VIM, ACTB | - Derived from tumor core - Intermediate phenotype - Associated with cytoskeletal and ribosomal protein expression | |||
Pe2 EC | CCL3, CCL4, CCL4L2, HLA-DRB1, HLA-DRA, HLA-DPA1, HLA-DPB1, HLA-DQB1 | - Immune-activated phenotype derived from nonmalignant tissue - Expression of inflammatory cytokines and MHC II-mediated antigen presentation genes | |||
Co3 EC | NR4A3, IL1B, IL1R1, SELE, SELP, VACM1 | - Derived from tumor core - Upregulation of immune-activated genes - Associated with inflammation and immune cell recruitment | |||
Pancancer | ESM1 tip EC | ESM1, NID2 | - Only resided in malignant tissue - Upregulation of glycolysis and OXPHOS | ||
ACKR1high HEV and venous EC | ACKR1, SELP | - ACKR1high endothelial venules and venous EC - Enriched in tumor | |||
CA4 capillary EC | CA4, CD36 | - Characterized by PLVAP and IGFBP7 | |||
FBLN5 arterial EC | FBLN5, GJA5 | - Upregulated fatty acid biosynthesis | |||
PROX1 lymphatic EC | PROX1, PDPN | - Increased fatty acid oxidation | |||
TECs | PLVAP, IGFBP7 | - Activation of HOXB pathways - Reduced carbonic acid metabolism |
