Stem Cell Reviews and Reports

, Volume 6, Issue 2, pp 307–316 | Cite as

Epiblast/Germ Line Hypothesis of Cancer Development Revisited: Lesson from the Presence of Oct-4+ Cells in Adult Tissues

  • Mariusz Z. Ratajczak
  • Dong-Myung Shin
  • Rui Liu
  • Wojtek Marlicz
  • Maciej Tarnowski
  • Janina Ratajczak
  • Magda Kucia
Article

Abstract

The morphology of several tumors mimics developmentally early tissues; tumors often express early developmental markers characteristic for the germ line lineage. Recently, our group identified a population of very small stem cells (SCs) in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “Very Small Embryonic/Epiblast-like Stem Cells (VSELs).” We hypothesized that these cells that express both epiblast and germ line markers are deposited during early gastrulation in developing tissues and organs and play an important role in the turnover of tissue-committed (TC) SCs. To support this, we envision that the germ line is not only the origin of SCs, but also remains as a scaffold or back-up for the SC compartment in adult life. Furthermore, we noticed that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique DNA methylation pattern in some developmentally crucial imprinted genes, which show hypomethylation or erasure of imprints in paternally methylated genes and hypermethylation of imprints in the maternally methylated. In pathological situations, however, we hypothesize that VSELs could be involved in the development of several malignancies. Therefore, potential involvement of VSELs in cancerogenesis could support century-old concepts of embryonic rest- or germ line-origin hypotheses of cancer development. However, we are aware that this working hypothesis requires further direct experimental confirmation.

Keywords

VSELs Oct-4 Cancer testis antigens Germ line 

Abbreviations

BM

Bone marrow

BMMNC

Bone marrow mononuclear cell

C/T

Cancer testis

DMR

Differently methylated region

dpc

Days post-conception

EGC

Embryonic germ cell

ESC

Embryonic stem cell

FACS

Fluorescence-activated cell sorting

FC

Flow cytometry

GC

Germ cell

HSC

Hematopoietic stem cell

ICM

Inner cell mass

Igf1R

Insulin-like growth factor 1 receptor

Igf2

Insulin-like growth factor 2

Igf2R

Igf2 receptor

ISS

ImageStream system

PGC

Primordial germ cell

PSC

Pluripotent stem cell

Rasgrf1

Ras protein-specific guanine nucleotide-releasing factor 1

SC

Stem cell

SSEA-1

Stage-specific embryonic antigen-1

TCSC

Tissue-committed stem cell

VSEL

Very small embryonic/epiblast-like stem cell

References

  1. 1.
    Kim, C. F., Jackson, E. L., Woolfenden, A. E., Lawrence, S., Babar, I., Vogel, S., et al. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 121, 823–835.CrossRefPubMedGoogle Scholar
  2. 2.
    Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432, 396–401.CrossRefPubMedGoogle Scholar
  3. 3.
    Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3, 730–737.CrossRefPubMedGoogle Scholar
  4. 4.
    Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111.CrossRefPubMedGoogle Scholar
  5. 5.
    Houghton, J., Stoicov, C., Nomura, S., Rogers, A. B., Carlson, J., Li, H., et al. (2004). Gastric cancer originating from bone marrow-derived cells. Science, 306, 1568–1571.CrossRefPubMedGoogle Scholar
  6. 6.
    Fang, D., Nguyen, T. K., Leishear, K., Finko, R., Kulp, A. N., Hotz, S., et al. (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Research, 65, 9328–9337.CrossRefPubMedGoogle Scholar
  7. 7.
    Welm, B., Behbod, F., Goodell, M. A., & Rosen, J. M. (2003). Isolation and characterization of functional mammary gland stem cells. Cell Proliferation, 36(Suppl 1), 17–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Boiani, M., & Scholer, H. R. (2005). Regulatory networks in embryo-derived pluripotent stem cells. Nature Reviews Molecular Cell Biology, 6, 872–884.CrossRefPubMedGoogle Scholar
  9. 9.
    O’Farrell, P. H., Stumpff, J., & Su, T. T. (2004). Embryonic cleavage cycles: how is a mouse like a fly? Current Biology, 14, R35–R45.PubMedGoogle Scholar
  10. 10.
    Brons, I. G., Smithers, L. E., Trotter, M. W., Rugg-Gunn, P., Sun, B., & Chuva de Sousa Lopes, S. M. (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature, 448, 191–195.CrossRefPubMedGoogle Scholar
  11. 11.
    Kucia, M., Reca, R., Campbell, F. R., Zuba-Surma, E., Majka, M., Ratajczak, J., et al. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia, 20, 857–869.CrossRefPubMedGoogle Scholar
  12. 12.
    Ratajczak, M. Z., Machalinski, B., Wojakowski, W., Ratajczak, J., & Kucia, M. (2007). A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia, 21, 860–867.PubMedGoogle Scholar
  13. 13.
    Ratajczak, M. Z., Zuba-Surma, E. K., Machalinski, B., Ratajczak, J., & Kucia, M. (2008). Very small embryonic-like (VSEL) stem cells: purification from adult organs, characterization, and biological significance. Stem Cells Review, 4, 89–99.CrossRefGoogle Scholar
  14. 14.
    Zuba-Surma, E. K., Kucia, M., Wu, W., Klich, I., Lillard, J. W., Jr., Ratajczak, J., et al. (2008). Very small embryonic-like stem cells are present in adult murine organs: ImageStream-based morphological analysis and distribution studies. Cytometry A, 73A, 1116–1127.CrossRefPubMedGoogle Scholar
  15. 15.
    Shin, D. M., Zuba-Surma, E. K., Wu, W., Ratajczak, J., Wysoczynski, M., Ratajczak, M. Z., et al. (2009). Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4(+) very small embryonic-like stem cells. Leukemia, 23, 2042–2051.Google Scholar
  16. 16.
    Beltrami, A. P., Cesselli, D., Bergamin, N., Marcon, P., Rigo, S., Puppato, E., et al. (2007). Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood, 110, 3438–3446.CrossRefPubMedGoogle Scholar
  17. 17.
    Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., Schwartz, R. E., Keene, C. D., Ortiz-Gonzalez, X. R., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418, 41–49.CrossRefPubMedGoogle Scholar
  18. 18.
    D’Ippolito, G., Diabira, S., Howard, G. A., Menei, P., Roos, B. A., & Schiller, P. C. (2004). Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. Journal of Cell Science, 117, 2971–2981.CrossRefPubMedGoogle Scholar
  19. 19.
    Pochampally, R. R., Smith, J. R., Ylostalo, J., & Prockop, D. J. (2004). Serum deprivation of human marrow stromal cells (hMSCs) selects for a subpopulation of early progenitor cells with enhanced expression of OCT-4 and other embryonic genes. Blood, 103, 1647–1652.CrossRefPubMedGoogle Scholar
  20. 20.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.CrossRefPubMedGoogle Scholar
  21. 21.
    Yu, H., Fang, D., Kumar, S. M., Li, L., Nguyen, T. K., Acs, G., et al. (2006). Isolation of a novel population of multipotent adult stem cells from human hair follicles. American Journal of Pathology, 168, 1879–1888.CrossRefPubMedGoogle Scholar
  22. 22.
    Jones, R. J., Wagner, J. E., Celano, P., Zicha, M. S., & Sharkis, S. J. (1990). Separation of pluripotent haematopoietic stem cells from spleen colony-forming cells. Nature, 347, 188–189.CrossRefPubMedGoogle Scholar
  23. 23.
    Donovan, P. J. (1998). The germ cell—the mother of all stem cells. International Journal of Developmental Biology, 42, 1043–1050.PubMedGoogle Scholar
  24. 24.
    Zwaka, T. P., & Thomson, J. A. (2005). A germ cell origin of embryonic stem cells? Development, 132, 227–233.CrossRefPubMedGoogle Scholar
  25. 25.
    McLaren, A. (2003). Primordial germ cells in the mouse. Developmental Biology, 262, 1–15.CrossRefPubMedGoogle Scholar
  26. 26.
    McLaren, A. (1992). Development of primordial germ cells in the mouse. Andrologia, 24, 243–247.PubMedCrossRefGoogle Scholar
  27. 27.
    Yamanaka, Y., Ralston, A., Stephenson, R. O., & Rossant, J. (2006). Cell and molecular regulation of the mouse blastocyst. Developmental Dynamics, 235, 2301–2314.CrossRefPubMedGoogle Scholar
  28. 28.
    De Felici, M., & McLaren, A. (1983). In vitro culture of mouse primordial germ cells. Experimental Cell Research, 144, 417–427.CrossRefPubMedGoogle Scholar
  29. 29.
    Yamazaki, Y., Mann, M. R., Lee, S. S., Marh, J., McCarrey, J. R., Yanagimachi, R., et al. (2003). Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proceedings of the National Academy of Sciences of the United States of America, 100, 12207–12212.CrossRefPubMedGoogle Scholar
  30. 30.
    Lee, J., Inoue, K., Ono, R., Ogonuki, N., Kohda, T., Kaneko-Ishino, T., et al. (2002). Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development, 129, 1807–1817.CrossRefPubMedGoogle Scholar
  31. 31.
    Mann, J. R. (2001). Imprinting in the germ line. Stem Cells, 19, 287–294.CrossRefPubMedGoogle Scholar
  32. 32.
    Lees-Murdock, D. J., & Walsh, C. P. (2008). DNA methylation reprogramming in the germ line. Epigenetics, 3, 5–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Delaval, K., & Feil, R. (2004). Epigenetic regulation of mammalian genomic imprinting. Current Opinion in Genetics and Development, 14, 188–195.CrossRefPubMedGoogle Scholar
  34. 34.
    Sasaki, H., Ishihara, K., & Kato, R. (2000). Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. Journal of Biochemistry, 127, 711–715.PubMedGoogle Scholar
  35. 35.
    Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425–432.CrossRefPubMedGoogle Scholar
  36. 36.
    Surani, M. A. (2001). Reprogramming of genome function through epigenetic inheritance. Nature, 414, 122–128.CrossRefPubMedGoogle Scholar
  37. 37.
    Donovan, P. J. (1994). Growth factor regulation of mouse primordial germ cell development. Current Topics in Developmental Biology, 29, 189–225.CrossRefPubMedGoogle Scholar
  38. 38.
    Matsui, Y., Zsebo, K., & Hogan, B. L. (1992). Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell, 70, 841–847.CrossRefPubMedGoogle Scholar
  39. 39.
    Resnick, J. L., Ortiz, M., Keller, J. R., & Donovan, P. J. (1998). Role of fibroblast growth factors and their receptors in mouse primordial germ cell growth. Biology of Reproduction, 59, 1224–1229.CrossRefPubMedGoogle Scholar
  40. 40.
    Shamblott, M. J., Axelman, J., Wang, S., Bugg, E. M., Littlefield, J. W., Donovan, P. J., et al. (1998). Derivation of pluripotent stem cells from cultured human primordial germ cells. Proceedings of the National Academy of Sciences of the United States of America, 95, 13726–13731.CrossRefPubMedGoogle Scholar
  41. 41.
    Kono, T., Obata, Y., Wu, Q., Niwa, K., Ono, Y., Yamamoto, Y., et al. (2004). Birth of parthenogenetic mice that can develop to adulthood. Nature, 428, 860–864.CrossRefPubMedGoogle Scholar
  42. 42.
    Kato, Y., Rideout, W. M., 3rd, Hilton, K., Barton, S. C., Tsunoda, Y., & Surani, M. A. (1999). Developmental potential of mouse primordial germ cells. Development, 126, 1823–1832.PubMedGoogle Scholar
  43. 43.
    Durcova-Hills, G., & Surani, A. (2008). Reprogramming primordial germ cells (PGC) to embryonic germ (EG) cells. Curr Protoc Stem Cell Biol, Chapter 1:Unit1A 3Google Scholar
  44. 44.
    Kaneda, A., Wang, C. J., Cheong, R., Timp, W., Onyango, P., Wen, B., et al. (2007). Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proceedings of the National Academy of Sciences of the United States of America, 104, 20926–20931.CrossRefPubMedGoogle Scholar
  45. 45.
    Hartmann, W., Koch, A., Brune, H., Waha, A., Schuller, U., Dani, I., et al. (2005). Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. American Journal of Pathology, 166, 1153–1162.PubMedGoogle Scholar
  46. 46.
    Hao, Y., Crenshaw, T., Moulton, T., Newcomb, E., & Tycko, B. (1993). Tumour-suppressor activity of H19 RNA. Nature, 365, 764–767.CrossRefPubMedGoogle Scholar
  47. 47.
    Pollak, M. (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nature Reviews Cancer, 8, 915–928.CrossRefPubMedGoogle Scholar
  48. 48.
    Font de Mora, J., Esteban, L. M., Burks, D. J., Nunez, A., Garces, C., Garcia-Barrado, M. J., et al. (2003). Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. EMBO Journal, 22, 3039–3049.CrossRefPubMedGoogle Scholar
  49. 49.
    Oosterhuis, J. W., & Looijenga, L. H. (2005). Testicular germ–cell tumours in a broader perspective. Nature Reviews Cancer, 5, 210–222.CrossRefPubMedGoogle Scholar
  50. 50.
    Macchiarini, P., & Ostertag, H. (2004). Uncommon primary mediastinal tumours. Lancet Oncology, 5, 107–118.CrossRefPubMedGoogle Scholar
  51. 51.
    Andrews, P. W., Matin, M. M., Bahrami, A. R., Damjanov, I., Gokhale, P., & Draper, J. S. (2005). Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochemical Society Transactions, 33, 1526–1530.CrossRefPubMedGoogle Scholar
  52. 52.
    Sigalotti, L., Covre, A., Zabierowski, S., Himes, B., Colizzi, F., Natali, P. G., et al. (2008). Cancer testis antigens in human melanoma stem cells: expression, distribution, and methylation status. Journal of Cellular Physiology, 215, 287–291.CrossRefPubMedGoogle Scholar
  53. 53.
    Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T., & Old, L. J. (2005). Cancer/testis antigens, gametogenesis and cancer. Nature Reviews Cancer, 5, 615–625.CrossRefPubMedGoogle Scholar
  54. 54.
    Ratajczak, M. Z., Shin, D. M., & Kucia, M. (2009). Very small embryonic/epiblast-like stem cells: a missing link to support the germ line hypothesis of cancer development? American Journal of Pathology, 174, 1985–1992.CrossRefPubMedGoogle Scholar
  55. 55.
    Hotakainen, K., Ljungberg, B., Haglund, C., Nordling, S., Paju, A., & Stenman, U. H. (2003). Expression of the free beta-subunit of human chorionic gonadotropin in renal cell carcinoma: prognostic study on tissue and serum. International Journal of Cancer, 104, 631–635.CrossRefGoogle Scholar
  56. 56.
    Cheng, L. (2004). Establishing a germ cell origin for metastatic tumors using OCT4 immunohistochemistry. Cancer, 101, 2006–2010.CrossRefPubMedGoogle Scholar
  57. 57.
    Barr, F. G. (1997). Molecular genetics and pathogenesis of rhabdomyosarcoma. Journal of Pediatric Hematology/Oncology, 19, 483–491.CrossRefPubMedGoogle Scholar
  58. 58.
    Liu, C., Chen, Z., Chen, Z., Zhang, T., & Lu, Y. (2006). Multiple tumor types may originate from bone marrow-derived cells. Neoplasia, 8, 716–724.CrossRefPubMedGoogle Scholar
  59. 59.
    Hernando, E. (2008). Cancer. Aneuploidy advantages? Science, 322, 692–693.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Mariusz Z. Ratajczak
    • 1
  • Dong-Myung Shin
    • 1
  • Rui Liu
    • 1
  • Wojtek Marlicz
    • 2
  • Maciej Tarnowski
    • 1
  • Janina Ratajczak
    • 1
  • Magda Kucia
    • 1
  1. 1.Stem Cell Institute at the James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of PathophysiologyPomeranian Medical UniversitySzczecinPoland

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