… the century-old theory of cancer cell fusion with tumor-associated leukocytes such as macrophages is really the only complete theory we have – potentially explaining most, if not all, aspects of metastasis, and particularly its initiation.
In this series of posts I’m trying to summarize some modern concepts describing the connection between different populations of bone marrow cells and cancer progression. Today I’m going to talk about the fusion phenomenon.
Fusion between bone marrow cells and other somatic cells in our body (heterotypic fusion) is one of the hottest and controversial topics in adult stem cell biology. In 2003 the heterotypic fusion phenomenon was described for the first time for bone marrow cells and mature specialized cells from different tissues – hepatocytes, cardiomyocytes and neurons. Last few years of research brought us to the conclusion that both lymphoid and myeloid lineages contribute to fusion hybrids, but almost exclusively in response to injuries or inflammation.
One more pathological process where heterotypic fusion was proposed as possible mechanism that occurs in cancer progression and metastasis. The most prominent research in this direction was done in John Pawelek lab. at Yale University. The hypothesis that describes leukocytes – tumor cell fusion has a very long history, summarized in this review. I’d like to look at the modern status of this concept and some human data.
Several laboratories reported that fusion hybrids adopt leukocyte’s ability to migrate and uncontrolled cell division from cancer cell. Fusion with cancer cells was described for epithelial, stromal cells, endothelial and different hematopoietic cells, mostly macrophages. The mechanisms underlying this phenomenon could be different (phagocytosis, virus-mediated, inflammation…) and still poorly understood. The fusion also proposed as a possible mechanism of cancer stem cell origin.
A model for generation of metastatic phenotype following fusion of a melanoma cell with a macrophage:
(The cartoon is courtesy of Dr. John Pawelek, Yale School of Medicine. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer 2008;8:377-386 doi:10.1038/nrc2371, copyright 2008)
About studying fusion concept of metastasis in human John Pawelek said:
… we turned to studying malignancies developing secondarily in individuals who had previously received an allogeneic bone marrow transplant – a new source of white blood cells for the patient. In two out of two cases studied in our laboratory so far, we found genes from the transplanted white blood cells in at least some of the patient tumor cells, indicating that it was most likely that fusion with white blood cells had occurred.
All studied human cases showed just incorporation of bone marrow cells into tumors, but other than fusion possible mechanisms of this phenomenon (such as direct transformation, transdifferentiation and developmental mimicry) can not be excluded.
Recent study published this year also did not dissect the mechanisms of incorporation of bone marrow cells in progressive cancer after hematopoietic stem cell transplantation. Anne Janin used short-term repeated (STR) sequence PCR in complement to FISH technique for donor versus recipient genetic material detection. No mixing origin DNA (donor + recipient) but only donor DNA was detected in tumors. According another recent study, in some tumors we can see only incorporation of donor’s bone marrow derived cells but not their neoplastic transformation of fusion. So far we have only one definitely proven clinical case of macrophage – cancer cell fusion in a myeloma patient.
Thus, even recent implications of “cell fusion as the mechanism for genetic material transfer in a clinical setting” and donor-derived bone marrow cells in cancer progression were made, we still can not claim that bone marrow derived or blood cell – cancer cell fusion is essential for metastasis in human.
I’ll finish with the quote:
Tumour cell–BMDC fusion as a source of metastatic cells would imply that prevention of fusion or of early, ratelimiting post-fusion events might prevent metastasis.
The cancer cell–BMDC fusion theory presents a unifying explanation for tumour progression. It seems that this theory is not only possible but likely to be correct to at least some degree, with the remaining question being how extensively does it contribute to progression of human cancers?
Pawelek JM. Cancer-cell fusion with migratory bone-marrow-derived cells as an explanation for metastasis: new therapeutic paradigms. Future Oncol. 2008 Aug;4(4):449-52
Pawelek JM, Chakraborty AK. Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 2008 May;8(5):377-86
Stem cells, cancer progression and metastasis (part I) – Systemic instigation
Stem cells, cancer progression and metastasis (part II) – angiogenesis
Stem cells, cancer progression and metastasis (part III) – premetastatic niche
How do traveling normal and malignant cells decide where to stay? Lessons from mammary cells
Pathotropism – what mediate stem cell tropism to tumor?
Stem cell niche in aging and cancer – summary from 50th annual American Society of Hematology meeting