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Cell Fusion in Cancer
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Cell Fusion in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2016) | Viewed by 52047

Special Issue Editors

Prof. Dr. Thomas Dittmar

E-Mail Website
Guest Editor
Chair of Immunology, Witten/Herdecke University, 58448 Witten, Germany
Interests: cell fusion; breast cancer; stem cells; macrophages; inflammation; metastasis; drug resistance
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lajos Kemény

E-Mail Website
Guest Editor
Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary
Interests: skin tumors; melanoma; keratinocyte; fibroblast; inflammation; immunotherapy

Special Issue Information

Dear Colleagues,

There is a growing body of evidence pointing to the pivotal impact of cell fusion events among tumor cells and normal cells, such as macrophages, stem cells, and fibroblasts, in fostering cancer progression, due to the evolution of unique hybrid cells exhibiting unique novel properties, such as an increased metastatogenic capacity and/or an enhanced drug resistance. Even though this has been well known for decades, we now start to understand the mechanisms, conditions, and factors directing the merging of two individual cells. A key element in the fusion cuisine inside a tumor is the chronically inflamed cancer microenvironment being attributed to the chaotic tumor architecture, a persistent death of tumor cells due to hypoxia and malnutrition and the sustained activation of “wound-healing” tumor-associated macrophages. The latter cell population does not only generate a tumor-friendly milieu due to secretion of growth factors, pro-angiogenic factors, and immune suppressive cytokines, but also facilitates wound healing via cell fusion (representing a common mechanism how “foreign” cells could adopt tissue function). In summary, the initiation of a physiological process within a pathophysiological environment initiates a fatal feedback loop: tumor progression is driven by the chronically inflamed microenvironment, which fosters cell fusion events among tumor cells and normal cells, which in turn contributes to tumor progression. The knowledge of this fatal feedback loop, as well as the increasing understanding how cell fusion is triggered, will help to develop novel anti-cell fusion and anti-cancer (stem) cell therapies.

This Special Issue, “Cell Fusion in Cancer”, will provide an overview of recent research activities and review articles dealing with the impact of tumor cell × normal cell hybridization in cancer progression. Original papers and review articles are all welcome.

Prof. Dr. Thomas Dittmar
Prof. Dr. Lajos Kemeny
Guest Editors

Manuscript Submission Information

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Keywords

  • cell fusion
  • neoplasia
  • breast cancer
  • melanoma
  • stem cells
  • macrophages
  • fibroblasts
  • inflammation
  • metastasis
  • drug resistance

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Published Papers (7 papers)

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Research

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2232 KiB  
Article
Melanoma-Derived BRAFV600E Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion
by Zsuzsanna Kurgyis, Lajos V. Kemény, Tünde Buknicz, Gergely Groma, Judit Oláh, Ádám Jakab, Hilda Polyánka, Kurt Zänker, Thomas Dittmar, Lajos Kemény and István B. Németh
Int. J. Mol. Sci. 2016, 17(6), 980; https://doi.org/10.3390/ijms17060980 - 21 Jun 2016
Cited by 13 | Viewed by 5278
Abstract
Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that [...] Read more.
Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAFV600E melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAFV600E protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAFV600E with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAFV600E mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAFV600E mutation or protein in the peritumoral stroma of BRAFWT melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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4763 KiB  
Article
Melanoma Cells Can Adopt the Phenotype of Stromal Fibroblasts and Macrophages by Spontaneous Cell Fusion in Vitro
by Lajos V. Kemény, Zsuzsanna Kurgyis, Tünde Buknicz, Gergely Groma, Ádám Jakab, Kurt Zänker, Thomas Dittmar, Lajos Kemény and István B. Németh
Int. J. Mol. Sci. 2016, 17(6), 826; https://doi.org/10.3390/ijms17060826 - 2 Jun 2016
Cited by 26 | Viewed by 6788
Abstract
After the removal of primary cutaneous melanoma some patients develop local recurrences, even after having histologically tumor-free re-excision. A potential explanation behind this phenomenon is that tumor cells switch their phenotype, making their recognition via standard histopathological assessments extremely difficult. Tumor-stromal cell fusion [...] Read more.
After the removal of primary cutaneous melanoma some patients develop local recurrences, even after having histologically tumor-free re-excision. A potential explanation behind this phenomenon is that tumor cells switch their phenotype, making their recognition via standard histopathological assessments extremely difficult. Tumor-stromal cell fusion has been proposed as a potential mechanism for tumor cells to acquire mesenchymal traits; therefore, we hypothesized that melanoma cells could acquire fibroblast- and macrophage-like phenotypes via cell fusion. We show that melanoma cells spontaneously fuse with human dermal fibroblasts and human peripheral blood monocytes in vitro. The hybrid cells’ nuclei contain chromosomes from both parental cells and are indistinguishable from the parental fibroblasts or macrophages based on their morphology and immunophenotype, as they could lose the melanoma specific MART1 marker, but express the fibroblast marker smooth muscle actin or the macrophage marker CD68. Our results suggest that, by spontaneous cell fusion in vitro, tumor cells can adopt the morphology and immunophenotype of stromal cells while still carrying oncogenic, tumor-derived genetic information. Therefore, melanoma–stromal cell fusion might play a role in missing tumor cells by routine histopathological assessments. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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4294 KiB  
Article
Hybrid Cells Derived from Human Breast Cancer Cells and Human Breast Epithelial Cells Exhibit Differential TLR4 and TLR9 Signaling
by Songül Tosun, Sabrina Fried, Bernd Niggemann, Kurt S. Zänker and Thomas Dittmar
Int. J. Mol. Sci. 2016, 17(5), 726; https://doi.org/10.3390/ijms17050726 - 13 May 2016
Cited by 4 | Viewed by 6178
Abstract
TLRs are important receptors of cells of the innate immune system since they recognize various structurally conserved molecular patterns of different pathogens as well as endogenous ligands. In cancer, the role of TLRs is still controversial due to findings that both regression and [...] Read more.
TLRs are important receptors of cells of the innate immune system since they recognize various structurally conserved molecular patterns of different pathogens as well as endogenous ligands. In cancer, the role of TLRs is still controversial due to findings that both regression and progression of tumors could depend on TLR signaling. In the present study, M13SV1-EGFP-Neo human breast epithelial cells, MDA-MB-435-Hyg human breast cancer cells and two hybrids M13MDA435-1 and -3 were investigated for TLR4 and TLR9 expression and signaling. RT-PCR data revealed that LPS and CpG-ODN induced the expression of pro-inflammatory cytokines, like IFN-β, TNF-α, IL-1β and IL-6 in hybrid cells, but not parental cells. Interestingly, validation of RT-PCR data by Western blot showed detectable protein levels solely after LPS stimulation, suggesting that regulatory mechanisms are also controlled by TLR signaling. Analysis of pAKT and pERK1/2 levels upon LPS and CpG-ODN stimulation revealed a differential phosphorylation pattern in all cells. Finally, the migratory behavior of the cells was investigated showing that both LPS and CpG-ODN potently blocked the locomotory activity of the hybrid cells in a dose-dependent manner. In summary, hybrid cells exhibit differential TLR4 and TLR9 signaling. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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Review

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411 KiB  
Review
Cancer Cell Fusion: Mechanisms Slowly Unravel
by Felicite K. Noubissi and Brenda M. Ogle
Int. J. Mol. Sci. 2016, 17(9), 1587; https://doi.org/10.3390/ijms17091587 - 21 Sep 2016
Cited by 41 | Viewed by 6258
Abstract
Although molecular mechanisms and signaling pathways driving invasion and metastasis have been studied for many years, the origin of the population of metastatic cells within the primary tumor is still not well understood. About a century ago, Aichel proposed that cancer cell fusion [...] Read more.
Although molecular mechanisms and signaling pathways driving invasion and metastasis have been studied for many years, the origin of the population of metastatic cells within the primary tumor is still not well understood. About a century ago, Aichel proposed that cancer cell fusion was a mechanism of cancer metastasis. This hypothesis gained some support over the years, and recently became the focus of many studies that revealed increasing evidence pointing to the possibility that cancer cell fusion probably gives rise to the metastatic phenotype by generating widespread genetic and epigenetic diversity, leading to the emergence of critical populations needed to evolve resistance to the treatment and development of metastasis. In this review, we will discuss the clinical relevance of cancer cell fusion, describe emerging mechanisms of cancer cell fusion, address why inhibiting cancer cell fusion could represent a critical line of attack to limit drug resistance and to prevent metastasis, and suggest one new modality for doing so. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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1196 KiB  
Review
Cell Fusion in the War on Cancer: A Perspective on the Inception of Malignancy
by Jeffrey L. Platt, Xiaofeng Zhou, Adam R. Lefferts and Marilia Cascalho
Int. J. Mol. Sci. 2016, 17(7), 1118; https://doi.org/10.3390/ijms17071118 - 13 Jul 2016
Cited by 26 | Viewed by 6029
Abstract
Cell fusion occurs in development and in physiology and rarely in those settings is it associated with malignancy. However, deliberate fusion of cells and possibly untoward fusion of cells not suitably poised can eventuate in aneuploidy, DNA damage and malignant transformation. How often [...] Read more.
Cell fusion occurs in development and in physiology and rarely in those settings is it associated with malignancy. However, deliberate fusion of cells and possibly untoward fusion of cells not suitably poised can eventuate in aneuploidy, DNA damage and malignant transformation. How often cell fusion may initiate malignancy is unknown. However, cell fusion could explain the high frequency of cancers in tissues with low underlying rates of cell proliferation and mutation. On the other hand, cell fusion might also engage innate and adaptive immune surveillance, thus helping to eliminate or retard malignancies. Here we consider whether and how cell fusion might weigh on the overall burden of cancer in modern societies. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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4269 KiB  
Review
Dendritic-Tumor Fusion Cell-Based Cancer Vaccines
by Shigeo Koido
Int. J. Mol. Sci. 2016, 17(6), 828; https://doi.org/10.3390/ijms17060828 - 26 May 2016
Cited by 53 | Viewed by 8389
Abstract
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells [...] Read more.
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4+ and CD8+ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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885 KiB  
Review
The Dark Side of Cell Fusion
by Daniel Bastida-Ruiz, Kylie Van Hoesen and Marie Cohen
Int. J. Mol. Sci. 2016, 17(5), 638; https://doi.org/10.3390/ijms17050638 - 28 Apr 2016
Cited by 70 | Viewed by 12153
Abstract
Cell fusion is a physiological cellular process essential for fertilization, viral entry, muscle differentiation and placental development, among others. In this review, we will highlight the different cancer cell-cell fusions and the advantages obtained by these fusions. We will specially focus on the [...] Read more.
Cell fusion is a physiological cellular process essential for fertilization, viral entry, muscle differentiation and placental development, among others. In this review, we will highlight the different cancer cell-cell fusions and the advantages obtained by these fusions. We will specially focus on the acquisition of metastatic features by cancer cells after fusion with bone marrow-derived cells. The mechanism by which cancer cells fuse with other cells has been poorly studied thus far, but the presence in several cancer cells of syncytin, a trophoblastic fusogen, leads us to a cancer cell fusion mechanism similar to the one used by the trophoblasts. The mechanism by which cancer cells perform the cell fusion could be an interesting target for cancer therapy. Full article
(This article belongs to the Special Issue Cell Fusion in Cancer)
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