Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

Abstract

Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/β-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-β (TGF-β)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.

Keywords: Hedgehog; JAK/STAT signaling; NF-κB; Notch; PI3K/Akt/mTOR signaling; Wnt/β-catenin pathway; cancer stem cells; cell signaling; colorectal; targeted therapy.

FIGURE 1

The Wnt/β‐catenin signaling pathway. In the absence of Wnt signaling, β‐catenin is bound to a multimeric protein complex that contains APC, GSK‐3β, axin‐1 and CK1α, leading to proteasomal degradation of β‐catenin. In the presence of Wnt signaling, the destruction of the complex function is interrupted. Wnt binds to LRP5/6 and FZD and inhibits the activity of the multimeric protein complex, which makes β‐catenin enter the nucleus, with subsequent translocation to the nucleus, binds to TCF/LEF to form a complex, and then recruits cofactors to initiate downstream gene expression. Abbreviations: APC, adenomatous polyposis coli; CK1α, casein kinase 1α; DVL, dishevelled; EGCG, epigallocatechin gallate; FZD, seven‐pass transmembrane receptor Frizzled; GSK‐3β, glycogen synthase kinase‐3 beta; LEF; lymphoid enhancer factor; LGR5, leucine‐rich repeat‐containing G‐protein‐coupled receptor 5; LRP5/6, single‐pass low‐density lipoprotein receptor‐related protein 5 or 6; MYC, MYC proto‐oncogene, bHLH transcription factor; RSPO, R‐spondin; TCF, T‐cell factor; TNIK, TRAF2‐ and NCK‐interacting kinase; Wnt, wingless

FIGURE 2

The Notch signaling pathway. The Notch single‐stranded pathways undergo proteolytic processing in the Golgi complex, which is furin protease‐mediated (S1 cleavage). The receptor is transported to the cell surface membrane. The extracellular domain of the Notch receptor in the signaling cell binds to the Notch ligands (Delta and Jagged) expressed by the adjacent cell. This induces the second proteolytic step by ADAM/TACE metalloproteases and γ‐secretase, which releases the intracellular Notch domain that translocates to the nucleus and then binds to the CSL transcription factor and activates the expression of Notch target genes. Abbreviations: ADAM, a disintegrin and metallopeptidase; CSL, CBF1 suppressor of hairless LAG1; MYC, MYC proto‐oncogene, bHLH transcription factor; SOX9, SRY‐box transcription factor 9; TACE, tumor necrosis factor‐alpha converting enzyme

FIGURE 3

The Hedgehog signaling pathway. In canonical HH signaling, HH ligands (SHH, IHH or DHH) bind to the PTCH transmembrane receptor, which relieves the inhibition of the transmembrane protein SMO and induces the GLI family of transcription factors (GLI1, GLI2, and GLI3) to enter the nucleus to regulate downstream gene transcription. Abbreviations: CDK, cyclin‐dependent kinase; DHH, desert hedgehog; HH, hedgehog; IHH, Indian hedgehog; MMP, matrix metalloproteinase; MYC, MYC proto‐oncogene, bHLH transcription factor; PTCH, patched; SHH, sonic hedgehog; SMO, smoothened; SNAI1, snail family transcriptional repressor 1

FIGURE 4

The NF‐κB signaling pathway. In the canonical pathway, the inhibitory protein IκB inhibits the translocation of the p65/p50 and c‐Rel/p50 dimers to the cell nucleus. The ubiquitination of IκB and its subsequent degradation release these proteins to be translocated to the cell nucleus, leading to the activation of the target genes. In the non‐canonical pathway, NIK induces the ubiquitination of p100 and its subsequent processing by proteasomes in p52. Then, RelB/p52 is translocated to the cell nucleus to activate the target genes. Abbreviations: ABL, ABL proto‐oncogene 1, non‐receptor tyrosine kinase; BAFF, B cell‐activating factor; BCR, BCR activator of RhoGEF and GTPase; BMP‐2, bone morphogenetic protein‐2; CCL19, C‐C motif chemokine ligand 19; CIAP1, cellular inhibitor of apoptosis protein 1; ICAM1, intercellular adhesion molecule 1; IKK, inhibitor of NF‐κB kinase; IκB, inhibitor of NF‐κB; Kras, Kirsten rat sarcoma viral oncogene homolog; LPS, lipopolysaccharide; LTβR, lymphotoxin beta receptor; MMP9, matrix metalloproteinase 9; MYC, MYC proto‐oncogene, bHLH transcription factor; NF‐κB, nuclear factor kappa B; NIK, NF‐κB‐inducing kinase; RANK, receptor activator of NF‐κB; TERT, telomerase reverse transcriptase; TNF, tumor necrosis factor

FIGURE 5

The JAK/STAT signaling pathway. JAK/STAT signaling starts with the interaction of cytokines or growth factors with their receptors, inducing the dimerization/oligomerization of these receptors and consequent activation. Activated JAKs autophosphorylate and phosphorylate their associated receptors. Therefore, cytoplasmic STATs bind to phosphorylated receptors and undergo homodimerization or heterodimerization after their phosphorylation, and they are able to translocate to the nucleus and activate the transcription of target genes. Abbreviations: JAK, Janus kinase; MMP2, matrix metalloproteinase 2; MYC, MYC proto‐oncogene, bHLH transcription factor; SOCS, suppressors of cytokine signaling; STAT, signal transducer and activator of transcription; VEGF, vascular endothelial growth factor

FIGURE 6

The PPAR signaling pathway. This signaling pathway begins through the interaction of a ligand with a GPCR, which triggers a series of signal conductions passed by AC, cAMP, and PKA until culminating in the activation and translocation of PPARα to the nucleus to modulate the expression of target genes. Abbreviations: AC, adenylyl cyclase; ACBP, acyl‐CoA‐binding protein; APO‐A5, apolipoprotein A5; cAMP, cyclic adenosine monophosphate; CPT‐2, carnitine palmitoyltransferase 2; GPCR, G protein‐coupled receptor; MMP1, matrix metalloproteinase 1; PGAR, PPAR gamma angiopoietin‐related gene; PKA protein kinase A; PPAR, peroxisome proliferator‐activated receptor; RXR, retinoid X receptor

FIGURE 7

The PI3K/Akt/mTOR signaling pathway. In the pathway cascade, after growth factors bind to their RTKs, the PI3K signaling pathway is activated, converting PIP2 into PIP3 until Akt activation is reached. This process is downregulated by PTEN. Akt, in turn, stimulates mTOR to phosphorylate target proteins to modulate gene expression. Abbreviations: EGFR, epidermal growth factor receptor; ERBB2, erb‐b2 receptor tyrosine kinase 2; GSK‐3β, glycogen synthase kinase‐3 beta; IGF‐1R, insulin‐like growth factor 1 receptor; mTOR, mechanistic target of rapamycin; MYC, MYC proto‐oncogene, bHLH transcription factor; PI3K, phosphatidyl‐inositol‐3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol (3,4,5)‐trisphosphate; PTEN, phosphatase and tensin homolog; RTKs, receptor tyrosine kinases; S6K1, ribosomal protein S6 kinase 1; SOX2, SRY‐box transcription factor 2

FIGURE 8

The TGF‐β/Smad signaling pathway. During activation, TGF‐β ligands bind to TGFBR2, which phosphorylates TGFBR1. TGFBR1 then phosphorylates receptor‐regulated Smads (Smad2/3) that bind to Smad4. This complex is translocated to the cell nucleus and acts as a transcription factor to regulate target gene expression. Abbreviations: SNAI1, snail family transcriptional repressor 1; TGFBR1, TGF‐β receptor type 1; TGFBR2, TGF‐β receptor type 2; TGF‐β, transforming growth factor‐β; TWIST1, twist family BHLH transcription factor 1; ZEB1, zinc finger e‐box binding homeobox 1