Cancer development, progression, and therapy: an epigenetic overview

Abstract

Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell-cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.

Figure 1

(A) Cancer progenitor cells and progression of metastatic cancer. a: hexagons with yellow dots represent normal cells; b: faded green, distorted hexagons with yellow dots represent cancer progenitor cells; c: progenitor cells are increasing in number; d: star-like brown cells represent the metastatic form of cancer cells, a mixed population of progenitor and adult cells; e: overgrowth of metastatic cells; f: both metastatic and adult progenitor cells leave site. Progression: Cancer progenitor cells develop from normal cells (a to b); After growth (b to c), they undergo EMT (c to d); Differentiation signals decrease and growth signals increase, producing a combination of progenitor and adult metastatic cancer cells (d to e); After the outgrowth of metastatic cells, translocation to a distant location occurs (e to f); (B) Model for the development of grade-specific cancers. Cancer progenitor cells pause at each grade of differentiation and proliferate from that grade while maintaining the ability to differentiate further; and (C) Model of the development of grade-specific cancers. Some cells progress further through differentiation than others, stop differentiation, and then proliferate, giving rise to clonal populations of cancer cells at distinct grades.

Figure 1

(A) Cancer progenitor cells and progression of metastatic cancer. a: hexagons with yellow dots represent normal cells; b: faded green, distorted hexagons with yellow dots represent cancer progenitor cells; c: progenitor cells are increasing in number; d: star-like brown cells represent the metastatic form of cancer cells, a mixed population of progenitor and adult cells; e: overgrowth of metastatic cells; f: both metastatic and adult progenitor cells leave site. Progression: Cancer progenitor cells develop from normal cells (a to b); After growth (b to c), they undergo EMT (c to d); Differentiation signals decrease and growth signals increase, producing a combination of progenitor and adult metastatic cancer cells (d to e); After the outgrowth of metastatic cells, translocation to a distant location occurs (e to f); (B) Model for the development of grade-specific cancers. Cancer progenitor cells pause at each grade of differentiation and proliferate from that grade while maintaining the ability to differentiate further; and (C) Model of the development of grade-specific cancers. Some cells progress further through differentiation than others, stop differentiation, and then proliferate, giving rise to clonal populations of cancer cells at distinct grades.

Figure 2

(A) Model of inhibition of transcription by methylation of CpG islands in gene promoter regions. HDAC: histone deacetylases; MBDP: methyl binding domain protein; Pol II: RNA polymerase II; and (B) Model linking histone methylation with DNA CpG methylation. DNMT1: DNA methyltransferase I; Me-CpG: methylated CpG residue; UHRF1: ubiquitin-like protein containing PHD and RING domains 1; H3K9: histone 3 lysine 9; Me: methylated. Open circles indicate unmethylated CpG residues; closed circles are methylated.