Meeting the Challenge of Targeting Cancer Stem Cells

Abstract

Notwithstanding cancer patients benefit from a plethora of therapeutic alternatives, drug resistance remains a critical hurdle. Indeed, the high mortality rate is associated with metastatic disease, which is mostly incurable due to the refractoriness of metastatic cells to current treatments. Increasing data demonstrate that tumors contain a small subpopulation of cancer stem cells (CSCs) able to establish primary tumor and metastasis. CSCs are endowed with multiple treatment resistance capabilities comprising a highly efficient DNA damage repair machinery, the activation of survival pathways, enhanced cellular plasticity, immune evasion and the adaptation to a hostile microenvironment. Due to the presence of distinct cell populations within a tumor, cancer research has to face the major challenge of targeting the intra-tumoral as well as inter-tumoral heterogeneity. Thus, targeting molecular drivers operating in CSCs, in combination with standard treatments, may improve cancer patients' outcomes, yielding long-lasting responses. Here, we report a comprehensive overview on the most significant therapeutic advances that have changed the known paradigms of cancer treatment with a particular emphasis on newly developed compounds that selectively affect the CSC population. Specifically, we are focusing on innovative therapeutic approaches including differentiation therapy, anti-angiogenic compounds, immunotherapy and inhibition of epigenetic enzymes and microenvironmental cues.

Keywords: anti-cancer therapies; cancer stem cells; epigenetic inhibitors; immunotherapy; metastasis.

FIGURE 1

The hallmarks of cancer stem cells. CSCs are endowed with a number of innate ad adaptive responses such as quiescence, EMT, increased DNA repair and detoxifying enzymes, metabostemness, immune evasion and over-expression of ABC transporters, which gave them the ability to survive changes in the microenvironment and anti-cancer therapies.

FIGURE 2

Tumor angiogenesis and metastatic process. Cancer cells secrete pro-angiogenic and pro-tumorigenic factors (MMPs, VEGF-A, HIF-1A, cytokines, chemokines, growth factors). VEGF-A activates endothelial cells (ECs) in tip cells, that direct the sprouting vessels, and stalk cells, implicated in vessel stability. Moreover, cancer cells-released cytokines activate cancer-associated fibroblasts (CAFs) and activated tumor-associated macrophages (TAMs), that in turn favor the intravasation of cancer stem cells (CSCs). Circulating cancer cells (CTCs) through the bloodstream reach target organ, extravasate and start to proliferate and disseminate. CSC, cancer stem cell; CTC, tumor circulating cells; DCC, differentiated cancer cell; CAF, cancer associated fibroblast; TAM, tumor associated macrophage; EC, endothelial cell; PC, pericyte cell.

FIGURE 3

The efficacy of immune-based therapies in the eradication of CSCs. The standard anti-cancer therapies are able to affect differentiated cancer cells (DCCs) while sparing CSCs. Novel immunotherapy approaches have shown promising therapeutic efficacy in several type of cancers. Combinations of checkpoint inhibitors (CTLA-4 and PD-1/PD-L1 pathway inhibitors) and CAR T cell transfer, in particular, efficiently eliminate the CSCs subpopulation.

FIGURE 4

Model showing the different layers of epigenetic regulation in CSCs and the potential therapeutic approaches. The chromatin fiber and the nucleosome are represented in the nucleus of a cancer stem cell. Epigenetic enzymes [writers (1), erasers (2), readers (3), and DNA methyltransferases (4)] are the principal actors in regulating the key survival pathways in CSCs, such as the Notch, Wnt and Hedgehog signaling. Moreover, epigenetic alterations guide the epithelial-mesenchymal transition (EMT) and the aberrant process of metastatization in CSCs, contributing to CSC resistance to therapy. Many of the latest generation compounds (epigenetic probes) have been designed to target the epigenetic enzymes involved in the CSC survival, maintenance, EMT and metastasis. DNMTi (DNA methyltransferase inhibitors): decitabine, azacitidine; HMTi (histone methyltransferase inhibitors) such as EZH2, DOT1L, and SETD8 inhibitors; HDACi (histone deacetylase inhibitors): vorinostat, romidepsin; BETi (bromodomain inhibitors): JQ1, I-BET762. Me, methylation; Ac, acetylation.