Bone Marrow Contributes to Epithelial Cancers in Mice and Humans as Developmental Mimicry

Bone marrow cells have the capacity to contribute to distant organs. We show that marrow also contributes to epithelial neoplasias of the small bowel, colon, and lung, but not the skin. In particular, epithelial neoplasias found in patients after hematopoietic cell transplantations demonstrate that human marrow incorporates into neoplasias by adopting the phenotype of the surrounding neoplastic environment. To more rigorously evaluate marrow contribution to epithelial cancer, we employed mouse models of intestinal and lung neoplasias, which revealed specifically that the hematopoietic stem cell and its progeny incorporate within cancer. Furthermore, this marrow involvement in epithelial cancer does not appear to occur by induction of stable fusion. Whereas previous claims have been made that marrow can serve as a direct source of epithelial neoplasia, our results indicate a more cautionary note, that marrow contributes to cancer as a means of developmental mimicry.

[1]  R. Czajka,et al.  Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood – preliminary report , 2007, Leukemia.

[2]  M. Ratajczak,et al.  The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis , 2006, Leukemia.

[3]  J Ratajczak,et al.  A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow , 2006, Leukemia.

[4]  Fan Zhang,et al.  Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes , 2006, Nature Medicine.

[5]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[6]  J. Pawelek.  Tumour-cell fusion as a source of myeloid traits in cancer. , 2005, The Lancet. Oncology.

[7]  E. Scott,et al.  SDF-1 is both necessary and sufficient to promote proliferative retinopathy. , 2005, The Journal of clinical investigation.

[8]  James R. Goldenring,et al.  Gastric Cancer Originating from Bone Marrow-Derived Cells , 2004, Science.

[9]  D. Steindler,et al.  Bone marrow transdifferentiation in brain after transplantation: a retrospective study , 2004, The Lancet.

[10]  M. Goodell.  Stem-cell “plasticity”: befuddled by the muddle , 2003 .

[11]  M. Grompe,et al.  Cell fusion is the principal source of bone-marrow-derived hepatocytes , 2003, Nature.

[12]  S. Badve,et al.  Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. , 2002, Experimental hematology.

[13]  I. Weissman,et al.  Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells , 2002, Science.

[14]  J. Inazawa,et al.  Damaged epithelia regenerated by bone marrow–derived cells in the human gastrointestinal tract , 2002, Nature Medicine.

[15]  E. Scott,et al.  Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization , 2002, Nature Medicine.

[16]  R. Poulsom,et al.  Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon , 2002, Gut.

[17]  D. Krause,et al.  Plasticity of marrow-derived stem cells. , 2003, Blood.

[18]  E. Scott,et al.  Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion , 2002, Nature.

[19]  A. Ruifrok,et al.  Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. , 2002, The New England journal of medicine.

[20]  Neil D. Theise,et al.  Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell , 2001, Cell.

[21]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[22]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[23]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[24]  Rebekah Gardner,et al.  Liver from bone marrow in humans , 2000, Hepatology.

[25]  R. Hoover,et al.  Solid cancers after bone marrow transplantation. , 1997, The New England journal of medicine.

[26]  G. Weil,et al.  Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[27]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[28]  J. Escourrou,et al.  Microchimerism: a stable state of low-ratio proliferation of allogeneic bone marrow. , 1977, Transplantation proceedings.