1 Oncogene 2012 Vol: 32(18):2247-2248. DOI: 10.1038/onc.2012.349

Reprogramming cancer cells: back to the future

Reprogramming healthy somatic cells into induced pluripotent stem cells (iPSCs) with four defined factors (Oct4, Sox2, c-Myc and Klf4) has been intensively investigated. However, reprogramming diseased cells such as cancer cells has fallen much behind. In this issue of Oncogene, Zhang et al. demonstrated that reprogrammed sarcoma cells with defined factors, as well as Nanog and Lin28, lost their tumorigenicity and dedifferentiated to mesenchymal stem cells (MSC) and hematopoietic stem cell (HSC)-like cells that can be terminally differentiated into mature connective tissues and red blood cells, suggesting sarcoma cells may be reversed back to a stage of common ancestor iPSC bifurcating for HSC and MSC ontogeny. It may, therefore, provide a novel strategy for cancer treatment via ancestor pluripotency induction

Mentions
Figures
Figure 1: Sarcoma cells can be reprogrammed with oncogene c-Myc and other defined factors into sarcoma iPSCs. In sarcoma iPSCs, gene promoters such as c-Myc promoter become hypermethylated, leading to c-Myc expression reduction. Sarcoma iPSCs can be further differentiated into mature connective tissues and red blood cells under terminal differentiation conditions.
Altmetric
References
  1. Muller LU, Daley GQ, Williams DA. Upping the ante: recent advances in direct reprogramming. Mol Ther 2009; 17: 947-953 , .
    • . . . Reprogramming with four defined factors, somatic cells can dedifferentiate into iPSCs and occasionally develop into tumors, which is attributed apparently to the oncogenic properties of c-Myc and Klf4.1, 2, 3 The immediate question is, therefore, what is the biological output we expect when proliferation-diseased cells like cancer cells are reprogrammed with defined factors including two oncogenes? Will cancer cells be more oncogenic if they become induced pluripotent cancer stem cell or bypass its genetic and epigenetic defects to be ‘normalized’ as iPSC which undergoes ontogeny terminal differentiation upon reprogramming? . . .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  2. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448: 313-317 , .
    • . . . Reprogramming with four defined factors, somatic cells can dedifferentiate into iPSCs and occasionally develop into tumors, which is attributed apparently to the oncogenic properties of c-Myc and Klf4.1, 2, 3 The immediate question is, therefore, what is the biological output we expect when proliferation-diseased cells like cancer cells are reprogrammed with defined factors including two oncogenes? Will cancer cells be more oncogenic if they become induced pluripotent cancer stem cell or bypass its genetic and epigenetic defects to be ‘normalized’ as iPSC which undergoes ontogeny terminal differentiation upon reprogramming? . . .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  3. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663-676 , .
    • . . . Reprogramming with four defined factors, somatic cells can dedifferentiate into iPSCs and occasionally develop into tumors, which is attributed apparently to the oncogenic properties of c-Myc and Klf4.1, 2, 3 The immediate question is, therefore, what is the biological output we expect when proliferation-diseased cells like cancer cells are reprogrammed with defined factors including two oncogenes? Will cancer cells be more oncogenic if they become induced pluripotent cancer stem cell or bypass its genetic and epigenetic defects to be ‘normalized’ as iPSC which undergoes ontogeny terminal differentiation upon reprogramming? . . .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  4. Hochedlinger K, Blelloch R, Brennan C, Yamada Y, Kim M, Chin L et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 2004; 18: 1875-1885 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  5. Ramos-Mejia V, Fraga MF, Menendez P. iPSCs from cancer cells: challenges and opportunities. Trends Mol Med 2012; 18: 245-247 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
    • . . . Epigenetic change has been suspected to be more relevant than any other factors in cancer cells’ resistance to iPSC development.5 However, reprogramming itself seems to induce epigenetic change, which might be responsible for reduced drug-resistance, reduced tumorigenicity and dedifferentiation detected in cancer-iPSCs . . .
  6. Carette JE, Pruszak J, Varadarajan M, Blomen VA, Gokhale S, Camargo FD et al. Generation of iPSCs from cultured human malignant cells. Blood 2010; 115: 4039-4042 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
    • . . . Despite its oncogenic property, c-Myc is indispensible in cancer cell reprogramming in many cases.6, 14 According to Zhang et al., all five sarcoma cell lines used in their study had intrinsic expression of c-Myc . . .
  7. Utikal J, Maherali N, Kulalert W, Hochedlinger K. Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 2009; 122: 3502-3510 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  8. Miyoshi N, Ishii H, Nagai K, Hoshino H, Mimori K, Tanaka F et al. Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci USA 2010; 107: 40-45 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  9. Chang G, Miao YL, Zhang Y, Liu S, Kou Z, Ding J et al. Linking incomplete reprogramming to the improved pluripotency of murine embryonal carcinoma cell-derived pluripotent stem cells. PLoS One 2010; 5: e10320 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  10. Choi SM, Liu H, Chaudhari P, Kim Y, Cheng L, Feng J et al. Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. Blood 2011; 118: 1801-1805 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  11. Hu K, Yu J, Suknuntha K, Tian S, Montgomery K, Choi KD et al. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 2011; 117: e109-e119 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  12. Lin SL, Chang DC, Chang-Lin S, Lin CH, Wu DT, Chen DT et al. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 2008; 14: 2115-2124 , .
    • . . . Although unidentified biological barriers may exist,4, 5 reprogramming of both solid and liquid tumors including gastric cancer, skin cancer, leukemia, B lymphoma, melanoma and mouse embryonic carcinoma has been reported by different groups.6, 7, 8, 9, 10, 11, 12 Loss of tumorigenicity by unknown mechanisms and induced dedifferentiation to pluriopotency seem to be common features of reprogrammed cells from different cancers. . . .
  13. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H et al. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306: 1568-1571 , .
    • . . . Although gastric cancer may originate from the hematopoietic lineage,13 it is unclear whether gastric cancer-iPSCs or other cancer-iPSCs can be reversed to the HSC stage as sarcoma-iPSCs do. . . .
  14. Berns EM, Klijn JG, van Putten WL, van Staveren IL, Portengen H, Foekens JA. c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Res 1992; 52: 1107-1113 , .
    • . . . Despite its oncogenic property, c-Myc is indispensible in cancer cell reprogramming in many cases.6, 14 According to Zhang et al., all five sarcoma cell lines used in their study had intrinsic expression of c-Myc . . .
  15. Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 1992; 257: 212-214 , .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  16. Shi YF, Sahai BM, Green DR. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 1989; 339: 625-626 , .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  17. Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 2002; 297: 102-104 , .
    • . . . It is worthwhile to mention, however, that exogenous expression of Klf4 and/or c-Myc at low levels is oncogenic,1, 2, 3 whereas overexpression of c-Myc induces apoptosis in T cells;15, 16 c-Myc causes tumors in immature osteoblasts, but induces apoptosis in differentiated osteocytes.17 It is unclear whether other types of cancer cells reprogrammed by different approaches rely on c-Myc's epigenetic restriction for dedifferentiation or terminal differentiation . . .
  18. Warrell RP, H de The, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-189 , .
    • . . . This is reminiscent of acute promyelocytic leukemia therapy with all-trans retinoic acid that induces the terminal differentiation of the leukemic promyelocytes to ‘normal cells’.18 It is a challenge to find how defined factors induce epigenetic changes in reprogrammed cancer cells, identify the de facto factor responsible for terminal differentiation in reprogrammed cancer cells and improve overall low reprogramming efficiency. . . .
Expand