Tumor-Cell Fusion—The Dark Matter Phenomenon

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 16718

Special Issue Editor

Special Issue Information

Dear Colleagues,

Cell Fusion is a widespread biological phenomenon, which is still controversially debated in human cancer biology. Do cell fusion events truly occur in human tumors? If so, do evolving hybrid cells (and their progenies) truly contribute to tumor progression as was postulated by Otto Aichel in 1911? Or is the cell fusion in human cancer hypothesis fiction or fact?

Of course, the major dilemma is that the ultimate proof supporting this hypothesis is still missing. So far, no data have been published clearly stating that, e.g., a) tumor-initiating cells originate from an initial cell fusion event; b) cell fusion drives tumor progression (e.g., by increasing tumor tissue heterogeneity); and/or c) cancer cell × normal cell hybrids are the seeds of secondary lesions and/or recurrences in humans. Hence, the cell fusion hypothesis resembles the dark matter theory.

However, what is the ultimate proof that cell fusion does not contribute to tumor progression and metastasis formation in human cancers? In fact, no one exactly knows how metastatic cancer cells truly originate, which also applies to the overall genomic instability of cancer cells. These properties of cancer cells could be explained by non-cell fusion dependent mechanisms, but they are also associated with the biological phenomenon of cell fusion. Moreover, within the past few years, several convincing studies have been published, clearly showing that true cancer cell × normal cell hybrids could be detected in human tumors, clearly indicating that cell fusion in human cancers is more fact than fiction.

The aim of this Special Issue is to provide and up-to-date overview about the current knowledge and findings in the field of tumor cell fusion.

Prof. Dr. Thomas Dittmar
Guest Editor

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Keywords

  • cell fusion
  • cancer
  • tumour progression
  • fusogens
  • macrophages
  • stem cells
  • metastasis

Published Papers (4 papers)

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Review

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11 pages, 734 KiB  
Review
Cell Fusion in Malignancy: A Cause or Consequence? A Provocateur or Cure?
by Jeffrey L. Platt and Marilia Cascalho
Cells 2019, 8(6), 587; https://doi.org/10.3390/cells8060587 - 14 Jun 2019
Cited by 14 | Viewed by 3492
Abstract
Cell fusion has been observed in malignancy, and cancer cells have been found especially apt to fuse with other cells. Investigation of human and experimental malignancies suggests spontaneous fusion of normal cells can induce manifold genetic changes and manifestations of malignant transformation. Fusion [...] Read more.
Cell fusion has been observed in malignancy, and cancer cells have been found especially apt to fuse with other cells. Investigation of human and experimental malignancies suggests spontaneous fusion of normal cells can induce manifold genetic changes and manifestations of malignant transformation. Fusion of transformed cells with other cells can promote the progression of cancer to more malignant forms. However, observations in various fields suggest cell fusion also potentially contributes to natural defenses against cancer. Thus, cell fusion potentially corrects genetic and/or phenotypic changes underlying malignant transformation. Cell fusion also might help nonmalignant cells in tumors thwart tumor growth. Perhaps most importantly, cell fusion may generate genetic changes that lead to the expression of neoantigens, provide the mass of neoantigen expression needed to elicit immunity, and promote the function of antigen-presenting cells in a way that favors protective immunity as a defense against malignancy. To the extent that cell fusion promotes cellular, tissue, and/or systemic resistance to malignancy, the propensity of tumor cells to fuse with other cells might constitute a natural defense against malignancy. Full article
(This article belongs to the Special Issue Tumor-Cell Fusion—The Dark Matter Phenomenon)
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9 pages, 1377 KiB  
Review
Leukocyte–Cancer Cell Fusion—Genesis of a Deadly Journey
by Greggory S. Laberge, Eric Duvall, Kay Haedicke and John Pawelek
Cells 2019, 8(2), 170; https://doi.org/10.3390/cells8020170 - 18 Feb 2019
Cited by 23 | Viewed by 4532
Abstract
According to estimates from the International Agency for Research on Cancer, by the year 2030 there will be 22 million new cancer cases and 13 million deaths per year. The main cause of cancer mortality is not the primary tumor itself but metastasis [...] Read more.
According to estimates from the International Agency for Research on Cancer, by the year 2030 there will be 22 million new cancer cases and 13 million deaths per year. The main cause of cancer mortality is not the primary tumor itself but metastasis to distant organs and tissues, yet the mechanisms of this process remain poorly understood. Leukocyte–cancer cell fusion and hybrid formation as an initiator of metastasis was proposed more than a century ago by the German pathologist Prof. Otto Aichel. This proposal has since been confirmed in more than 50 animal models and more recently in one patient with renal cell carcinoma and two patients with malignant melanoma. Leukocyte–tumor cell fusion provides a unifying explanation for metastasis. While primary tumors arise in a wide variety of tissues representing not a single disease but many different diseases, metastatic cancer may be only one disease arising from a common, nonmutational event: Fusion of primary tumor cells with leukocytes. From the findings to date, it would appear that such hybrid formation is a major pathway for metastasis. Studies on the mechanisms involved could uncover new targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Tumor-Cell Fusion—The Dark Matter Phenomenon)
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17 pages, 1532 KiB  
Review
Cell Fusion in Human Cancer: The Dark Matter Hypothesis
by Julian Weiler and Thomas Dittmar
Cells 2019, 8(2), 132; https://doi.org/10.3390/cells8020132 - 07 Feb 2019
Cited by 40 | Viewed by 5403
Abstract
Current strategies to determine tumor × normal (TN)-hybrid cells among human cancer cells include the detection of hematopoietic markers and other mesodermal markers on tumor cells or the presence of donor DNA in cancer samples from patients who had previously received an allogenic [...] Read more.
Current strategies to determine tumor × normal (TN)-hybrid cells among human cancer cells include the detection of hematopoietic markers and other mesodermal markers on tumor cells or the presence of donor DNA in cancer samples from patients who had previously received an allogenic bone marrow transplant. By doing so, several studies have demonstrated that TN-hybrid cells could be found in human cancers. However, a prerequisite of this cell fusion search strategy is that such markers are stably expressed by TN-hybrid cells over time. However, cell fusion is a potent inducer of genomic instability, and TN-hybrid cells may lose these cell fusion markers, thereby becoming indistinguishable from nonfused tumor cells. In addition, hybrid cells can evolve from homotypic fusion events between tumor cells or from heterotypic fusion events between tumor cells and normal cells possessing similar markers, which would also be indistinguishable from nonfused tumor cells. Such indistinguishable or invisible hybrid cells will be referred to as dark matter hybrids, which cannot as yet be detected and quantified, but which contribute to tumor growth and progression. Full article
(This article belongs to the Special Issue Tumor-Cell Fusion—The Dark Matter Phenomenon)
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Other

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5 pages, 197 KiB  
Perspective
The Fate of Fusions
by Gary Clawson
Cells 2019, 8(1), 13; https://doi.org/10.3390/cells8010013 - 29 Dec 2018
Cited by 9 | Viewed by 2794
Abstract
The concept of leukocyte-tumor cell fusion as a significant driver of cancer progression has been around a long time, and has garnered growing support over the last several years. The underlying idea seems quite simple and attractive: Fusion of tumor cells (with their [...] Read more.
The concept of leukocyte-tumor cell fusion as a significant driver of cancer progression has been around a long time, and has garnered growing support over the last several years. The underlying idea seems quite simple and attractive: Fusion of tumor cells (with their inherent genetic instability) with leukocytes, particularly macrophages, could produce hybrids with high invasive capabilities, greatly facilitating their metastatic dissemination, while potentially accelerating tumor cell heterogeneity. While there are a number of attractive features with this story on the surface, the various studies seem to leave us with a conundrum, namely, what is the fate of such fusions? Full article
(This article belongs to the Special Issue Tumor-Cell Fusion—The Dark Matter Phenomenon)
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