Cancer stem cells and strategies for targeted drug delivery

Abstract

Cancer stem cells (CSCs) are a small proportion of cancer cells with high tumorigenic activity, self-renewal ability, and multilineage differentiation potential. Standard anti-tumor therapies including conventional chemotherapy, radiation therapy, and molecularly targeted therapies are not effective against CSCs, and often lead to enrichment of CSCs that can result in tumor relapse. Therefore, it is hypothesized that targeting CSCs is key to increasing the efficacy of cancer therapies. In this review, CSC properties including CSC markers, their role in tumor growth, invasiveness, metastasis, and drug resistance, as well as CSC microenvironment are discussed. Further, CSC-targeted strategies including the use of targeted drug delivery systems are examined.

Keywords: Anti-tumor therapy; Cancer biology; Cancer stem cells (CSCs); Drug delivery system; Drug-resistance.

Fig. 1

Proposed models for cancer stem cell evolution. Hierarchically organized tumors (a) have a subpopulation of self-renewing cells maintaining the clonal population at the top of the pyramid while giving rise to larger number of progenitor cells ultimately differentiating into other cells in the tumor. The tumor formed has low heterogenicity. Clonal model (c) suggests that selective pressure and continued mutations give way to a highly aggressive population of cells which are tumor initiating and can also self-renew. With different cell phenotypes present, the tumor produced has a high heterogenicity. The unified model (b) suggests stem cell plasticity where cancer stem cells can transition between non-CSCs and CSCs given the right conditions. The resulting tumor is complex, has high heterogenicity and increased resistance to most anti-cancer therapies

Fig. 2

Mechanisms of therapy resistance in CSCs. ABC transporters: ABC transporters reduce the effective concentration of cytokines and administered chemotherapeutics in the cytoplasm. Microenvironment/Hippo: The tumor microenvironment (increased EMT, hypoxic conditions, inhibited Hippo pathway) contributes to increased stemness of CSCs. Epigenome: Instability of chromatin and changes in epigenetic modulators allow for phenotypic differentiation of CSCs. Exosomes: Exosomes promote a CSC phenotype in normal tumor cells by transporting MDR transport proteins to recipient drug sensitive cells. DNA damage repair (DDR): An increased DDR is observed in CSCs due to overexpression of proteins involved in repairing DNA damage (PARP-1, BRCA1, RAD 50, etc.). UPR/ERS: Endoplasmic reticulum stress (ERS) is characterized by presence of misfolded protein in the ER lumen. The unfolded protein response (UPR) signal transduction pathway which balances the ER protein folding is disturbed in the presence of certain physiological conditions (hypoxia, TME, unstable genome). Autophagy: Autophagy has been shown to increase CSC survival and aggressiveness by improving stress tolerance. Metabolism: CSCs can efficiently adapt metabolic pathways or switch pathways to maintain an energy source. This makes them thrive in adverse conditions and imparts resistance to most conventional anti-cancer treatments. Apoptosis evasion: CSCs evade apoptosis by regulating (or altering) apoptotic genes during transcription, translation or even post-translation. Figure adapted from [17]

Fig. 3

Link between CSCs, tumor metastasis and epithelial-mesenchymal transition (EMT)

Fig. 4

Potential approaches to combat multidrug resistance (MDR) in cancer stem cells. ABC – antigen binding cassette, RNAi – RNA interference, miRNA – microRNA, ASO – antisense oligonucleotides, CRISPR/Cas9 – Clustered randomly interspaced short palindromic repeats/Cas9

Fig. 5

Potential ways to target signaling pathways in cancer stem cells