Defined factors induce reprogramming of gastrointestinal cancer cells

Abstract

Although cancer is a disease with genetic and epigenetic origins, the possible effects of reprogramming by defined factors remain to be fully understood. We studied the effects of the induction or inhibition of cancer-related genes and immature status-related genes whose alterations have been reported in gastrointestinal cancer cells. Retroviral-mediated introduction of induced pluripotent stem (iPS) cell genes was necessary for inducing the expression of immature status-related proteins, including Nanog, Ssea4, Tra-1-60, and Tra-1-80 in esophageal, stomach, colorectal, liver, pancreatic, and cholangiocellular cancer cells. Induced cells, but not parental cells, possessed the potential to express morphological patterns of ectoderm, mesoderm, and endoderm, which was supported by epigenetic studies, indicating methylation of DNA strands and the histone H3 protein at lysine 4 in promoter regions of pluripotency-associated genes such as NANOG . In in vitro analysis induced cells showed slow proliferation and were sensitized to differentiation-inducing treatment, and in vivo tumorigenesis was reduced in NOD/SCID mice. This study demonstrated that pluripotency was manifested in induced cells, and that the induced pluripotent cancer (iPC) cells were distinct from natural cancer cells with regard to their sensitivity to differentiation-inducing treatment. Retroviral-mediated introduction of iPC cells confers higher sensitivity to chemotherapeutic agents and differentiation-inducing treatment.

Induced pluripotent stem cell-related genes influence biological behavior and 5-fluorouracil sensitivity of colorectal cancer cells

“…The successful artificial de-differentiation of adult somatic cells (Takahashi et al, 2007;Yu et al, 2007;Park et al, 2008) and cancer cells (Carette et al, 2010;Miyoshi et al, 2010) to an embryonic stem cell-like state by defined reprogramming factors, including OCT4, SOX2, KLF4, C-MYC, NANOG, and LIN28, has drawn growing attention to the putative resemblance between the laboratory generation of induced pluripotent stem/cancer (iPS/iPC) cells in vitro and the spontaneous generation of CSCs in vivo. We speculate that partial reactivation of the reprogramming factor set and inappropriate microenvironments may lead to a disordered self-renewal and differentiation capacity rather than regulated pluripotency.…”

Induced Pluripotency and Oncogenic Transformation Are Related Processes

“…Whatever the mechanism, which remains an open question, the fact that ROF were not able to differentiate as efficiently as iPSCs suggest that faithful reprogramming of cancer cells may require a different approach from that used in reprogramming noncancerous somatic cells, a notion supported by the reprogramming of melanoma cells using only miRNAs [58]. To date, a number of cancer cell types have been reprogrammed into iPS-like cells [59], including colorectal, pancreatic, hepatocellular carcinoma, and embryonal carcinoma [60]. It is probable that each specific type of cancer may require customized methods for reprogramming.…”

Xenopatients 2.0: Reprogramming the epigenetic landscapes of patient-derived cancer genomes

“…Different experimental results suggest that cancer cells can be reprogrammed to a non-tumoral fate that loses their malignancy. Miyoshi et al 80 reported that defined factors induced reprogramming of gastrointestinal cancer cells to demonstrate slow proliferation, sensitization to differentiation-inducing treatment, and reduced in vivo tumorigenesis in NOD/ SCID mice. However, these authors reported only xenograft formation with no histology or immunohistochemistry.…”