Dedifferentiation and reprogramming: origins of cancer stem cells

Abstract

Regenerative medicine aims to replace the lost or damaged cells in the human body through a new source of healthy transplanted cells or by endogenous repair. Although human embryonic stem cells were first thought to be the ideal source for cell therapy and tissue repair in humans, the discovery by Yamanaka and colleagues revolutionized the field. Almost any differentiated cell can be sent back in time to a pluripotency state by expressing the appropriate transcription factors. The process of somatic reprogramming using Yamanaka factors, many of which are oncogenes, offers a glimpse into how cancer stem cells may originate. In this review we discuss the similarities between tumor dedifferentiation and somatic cell reprogramming and how this may pose a risk to the application of this new technology in regenerative medicine.

Figure 1

Glioblastoma tumors induced by oncogenic lentivirus either in neurons or in glia in the cortex initially express differentiation markers (e.g., Tuj1 and GFAP, respectively), but as tumor progresses, these markers decrease and stem/progenitor markers become predominantly expressed (like nestin and Sox2) [20].

Figure 2

An astrocyte transduced with LV-Hras-shp53 dedifferentiates/reprograms to a progenitor/stem cell state, leading to tumorsphere formation. These tumorspheres when transplanted orthotopically in the brain of mice lead to glioma tumors. The same astrocytes transduced with a lentivector carrying the four transcription factors (Oct-4, Klf-4, Sox2, and myc) reprogram and form iPS colonies than when transplanted s.c. into mice develop teratomas.

Figure 3

Normal mechanism of neuronal differentiation: Neural stem cell can self-renew, go through an intermediate progenitor cell, and differentiate into oligodendrocytes, astrocytes, neurons, and endothelial cells. In the formation of glioblastoma, the transformed neurons, astrocytes, and possibly oligodendrocytes can dedifferentiate/reprogram to become cancer stem cells (CSCs), which can then continue to self-proliferate and differentiate to more transformed neurons and astrocytes. The transformed neurons and astrocytes can also transdifferentiate into endothelial cells (TDECs), which can again dedifferentiate to CSCs.