Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance

Table 1 Cancer stem cells and epithelial-mesenchymal transition targeted therapy

Cancer type	Biological mechanism(s) of resistance	Targeted therapy andtherapeutic functions	Clinical trial if any	Ref.
CRPC	Skp2 regulates CRPC through Twist-mediated oncogenic functions including EMT and CSCs acquisition	Genetic or pharmacological inactivation of Skp2 re-sensitize CRPC cells toward chemotherapies such as paclitaxel or doxorubicin	None	[40]
Lung cancer	High levels of circulating IGF1 lead to EMT induction and CSC maintenance	Use of IGF1R inhibitors sensitize cancer cells to killing effects of carboplatin, paclitaxel, docetaxel, and vinorelbine	Phase I trial	[41]
Ovarian cancer, advanced solid tumors	FAK linked with WNT, TGF-beta, Integrin and Hedgehog pathways, mediate cell invasion and metastasis	Anti-sense FAK oligonucleotides, adenoviral dominant-negative FAK-CD, FAK siRNA, pharmacological inhibitors affect tumor cells and microenvironment	Phase I trial	[42,43]
Invasive ductal breast cancer	Elevated expression of ABC drug transporters, induction of Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of EMT	Salinomycin promotes differentiation of CSCs, epithelial reprogramming of cells that had undergone EMT	Clinical pilot studies	[44]
Human lung epithelial cells	Activation of TGF-β/Smad signaling pathway, induction of EMT and therapy resistance	Use of drug, lerdelimumab, which acts as monoclonal antibody to TGF-β1	Preclinical	[45]
Renal cell carcinoma, malignant melanoma	Activation of TGF-β/Smad signaling pathway, induction of EMT and therapy resistance	Use of drug, GC1008, which acts as monoclonal antibody to TGF-β1	Phase I trial	[46]
Glioblastoma/anaplastic astrocytoma	Activation of TGF-β/Smad signaling pathway, induction of EMT and therapy resistance	Antisense oligodeoxynucleotide specific for the mRNA of human TGF-β2	Phase I/II trial	[47]
Renal cell carcinoma, advanced cancers	Inflammatory cytokines including TNF-α and IL6 promote EMT and tumor invasion	Infliximab, a TNF-α monoclonal blocking antibody suppresses the levels of IL6 and CCL2	Phase II trial	[48,49]
Metastatic gastric adenocarcinoma, recurrent and metastatic head and neck squamous cell carcinoma	Activation of NF-κB and TNF-α signaling	Bortezomib, a proteasome inhibitor suppresses NFκB activation	Phase II trial	[50,51]
Advanced solid tumors; advanced lung cancer	Increased expression of HIF-1α	Drug, PX-478 inhibits HIF1α expression Topotecan along with conventional chemotherapies such as cisplatin or bevacizumab inhibit HIF-1α expression	Phase I trial Phase I/II trial	[52,53]

CRPC: Castration-resistant prostate cancer; Skp2: S-phase protein kinase 2; EMT: Epithelial-mesenchymal transition; CSCs: Cancer stem cells; IGF1: Insulin-like growth factor 1; FAK: Focal adhesion kinase; TGF-beta: Transforming growth factor-beta; ABC: ATP-binding cassette; siRNA: Small interfering RNA; TNF-α: Tumor necrosis factor-α; IL6: Interleukin 6; NF-κB: Nuclear factor-κB; CCL2: C-C motif chemokine ligand 2; HIF-1α: Hypoxia inducible factor 1-alpha; PX-478: S-2-amino-3-[4’-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride.