Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies

Abstract

In vitro modeling of complex diseases is now a possibility with the use of patient-derived induced pluripotent stem (iPS) cells. Their stem cell properties, including self-renewal and their potential to virtually differentiate into any cell type, emphasize their importance as a translational tool for modeling disorders that so far have been limited by the unavailability of primary cell lines, animal models, or inaccessible human materials. Around 100 genes with germline mutations have been described to be responsible for cancer predisposition. Familial cancers are usually diagnosed earlier in life since these patients already carry the first transforming hit. Deriving iPS cells from patients suffering from familial cancers provides a valuable tool for understanding the mechanisms underlying pediatric cancer onset and progression since they require less mutation recurrence than adult cancers to develop. At the same time, some familial mutations are found in sporadic cases and are a valuable prognostic tool. Patient-derived iPS cells from germline malignancies can also create new tools in developing specific drugs with more personalized-therapy strategies.

Fig. 1. Approaches to generate pluripotent stem cells from cancer cells

(Upper part) Somatic cell nuclear transfer (SCNT) leads to reprogramming of the cancer cell nucleus. The nucleus of a cancer cell is microinjected into an enucleated mouse oocyte that further develops into a blastocyst. ES cells are isolated from the inner cell mass of the blastocyst. (Lower part) Due to ethical limitations involving using human pre-implantation embryos, reprogramming using the four Yamanaka factors (OSKM) has been extensively used for human cancer cell lines and somatic cells derived from patients. Retrovirus, Sendai virus, exosomes, and mRNA among other techniques can be used to deliver the factors and thereafter generate unlimited source of patient-derived iPS cells. ES embryonic stem, iPS induced pluripotent stem, OSKM Oct4, Sox2, Klf4, and c-Myc transcription factors

Fig. 2. Cellular reprogramming of cancer and somatic cells

a Cancer cells isolated from patients can be reprogrammed into iPS cells using the Yamanaka factors (OSKM). Thereafter, cancer-derived iPS cells can be differentiated into diverse relevant cell types for studying progression of the disease. The drawing exemplifies how cancer cell-derived iPS cells can be used to study tumor specification, develop in vitro cancer models and testing of novel potential targets for therapy. b Cancer patients carrying familial cancer predisposition mutations can be useful for understanding onset and tissue specificity of the disease. Somatic cells can be used for reprogramming into iPS cells that can be differentiated into any relevant cell type. This permits the development of in vitro and in vivo systems for modelling disease and use for potential identification of therapeutic targets. iPS induced pluripotent stem, OSKM Oct4, Sox2, Klf4, and c-Myc transcription factors

Fig. 3. Childhood cancer incidence and survival

a Global proportional distribution of childhood cancer incidence in age group 0–14 years, adapted from statistics presented in. b 5-year survival of the most common forms of childhood cancer diagnosed in European patients during 2000–2007, adapted from the Eurocare-5 study. ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, CNS central nervous system