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

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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.

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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

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Acknowledgments

This work is supported by NIH grants R01 CA106281-01 and R01 DK074720 and the Stella and Henry Hoenig Endowment to MZR NIH grant P20RR018733 from the National Center for Research Resources to MK and European Union structural funds, Innovative Economy Operational Program POIG. 01.01.02-00-109/09-00.

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Authors and Affiliations

  1. Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA

    Mariusz Z. Ratajczak, Dong-Myung Shin, Rui Liu, Maciej Tarnowski, Janina Ratajczak & Magda Kucia

  2. Department of Pathophysiology, Pomeranian Medical University, Szczecin, Poland

    Wojtek Marlicz

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  1. Mariusz Z. Ratajczak
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  2. Dong-Myung Shin
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Correspondence to Mariusz Z. Ratajczak or Magda Kucia.

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Ratajczak, M.Z., Shin, DM., Liu, R. et al. Epiblast/Germ Line Hypothesis of Cancer Development Revisited: Lesson from the Presence of Oct-4+ Cells in Adult Tissues. Stem Cell Rev and Rep 6, 307–316 (2010). https://doi.org/10.1007/s12015-010-9143-4

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