Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP)

Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells.

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Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo

Cancers ◽

10.3390/cancers13174496 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4496

Author(s):

Ralf Hass ◽

Juliane von der Ohe ◽

Thomas Dittmar

Keyword(s):

Cell Fusion ◽

Cancer Cell ◽

Selection Process ◽

Hybrid Cell ◽

Chromosomal Rearrangements ◽

Immune Surveillance ◽

Hybrid Cells ◽

Tumor Plasticity

The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge.

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Altered Tumor Plasticity after Different Cancer Cell Fusions with MSC

International Journal of Molecular Sciences ◽

10.3390/ijms21218347 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8347 ◽

Cited By ~ 1

Author(s):

Catharina Melzer ◽

Juliane von der Ohe ◽

Ralf Hass

Keyword(s):

Cancer Cells ◽

Cell Fusion ◽

Cancer Cell ◽

Human Cancer ◽

Selection Process ◽

Hybrid Cell ◽

Therapeutic Interventions ◽

Cellular Interactions ◽

Tumor Plasticity

While cell fusion demonstrates an important pathway during tissue development and regeneration of distinct organs, this process can also contribute to pathophysiological phenotypes during tumor progression. Hybrid cell formation after heterofusion between cancer cells and various other cell types within the tumor microenvironment is observed in vitro and in vivo. In particular, mesenchymal stroma/stem-like cells (MSC) perform diverse levels of communication with cancer cells by exhibiting anti- and pro-tumorigenic effects. During these cellular interactions, MSC can eventually fuse with cancer cells. Thereby, the newly generated disparate hybrid populations display aneuploidy associated with chromosomal instability. Based upon a subsequent post-hybrid selection process (PHSP), fused cancer cells can undergo apoptosis/necroptosis, senescence, dormancy, or a proliferative state by acquisition of new properties. Consequently, PHSP-surviving hybrid cancer cells demonstrate altered functionalities within the tumor tissue. This is accompanied by changes in therapeutic responsiveness and a different metastatic behavior. Accordingly, enhanced tumor plasticity interferes with successful therapeutic interventions and aggravates patient prognoses. The present review article focusses on fusion of MSC with different human cancer cells, in particular breast cancer populations and resulting characteristics of various cancer hybrid cells. Moreover, some mechanisms of cancer cell fusion are discussed together with multiple PHSP pathways.

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Spontaneous fusion of MSC with breast cancer cells can generate tumor dormancy

10.21203/rs.3.rs-321562/v1 ◽

2021 ◽

Author(s):

Catharina Melzer ◽

Juliane von der Ohe ◽

Tianjiao Luo ◽

Ralf Hass

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Fusion ◽

Cancer Cell ◽

Tumor Heterogeneity ◽

Breast Cancer Cells ◽

Tumor Development ◽

Cell Populations ◽

Hybrid Cells

Abstract Background: A variety of different tumors including breast cancer cells can closely interact with mesenchymal stroma/stem-like cells (MSC) in the tumor microenvironment eventually resulting in cell fusion and formation of new hybrid cancer cell populations displaying altered properties. Methods: Lentiviral-transduced MDA-MB-231 cherry breast cancer cells and MSC GFP were co-cultured and a resulting hybrid cancer cell population (MDA-MSC-hyb5) was isolated. Characterization was performed for marker expression and short tandem repeat (STR) fragment analysis compared to the parental cells. Moreover, in vivo tumor development and metastatic capacity of MDA-MSC-hyb5 was studied and unique properties were analyzed by RNA microarray expression analyses compared to other breast cancer hybrid populations. Potential chemotherapeutic sensitivity was carried out in tumor explant cultures of MDA-MSC-hyb5 cells. Results: Direct cellular interactions of MDA-MB-231 cherry breast cancer cells with human MSC GFP in a co-culture model resulted in spontaneous cell fusion by generation of MDA-MSC-hyb5 cherry GFP breast cancer hybrid cells. Proliferative capacity of MDA-MSC-hyb5 cells was about 1.8-fold enhanced when compared to the parental MDA-MB-231 cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231 cherry -induced tumor development in vivo within 18.8 days MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points up to about a half year later after injection NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors. Following tumor initiation, formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced as compared to MDA-MB-231 cells, however, some resistance e.g. for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during tumor development of MDA-MSC-hyb5 cells suggesting unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity. Conclusions: The spontaneous formation of cancer hybrid cell populations like MDA-MSC-hyb5 by cell fusion contributes to tumorigenic diversification by acquisition of new properties such as altered chemotherapeutic responsiveness. The unique tumor dormancy of MDA-MSC-hyb5 cells not observed in other breast cancer hybrid cells so far markedly increases tumor heterogeneity.

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In Vivo Cell Fusion between Mesenchymal Stroma/Stem-Like Cells and Breast Cancer Cells

Cancers ◽

10.3390/cancers11020185 ◽

2019 ◽

Vol 11 (2) ◽

pp. 185 ◽

Cited By ~ 17

Author(s):

Catharina Melzer ◽

Juliane von der Ohe ◽

Ralf Hass

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Fusion ◽

Breast Cancer Cells ◽

Rare Event ◽

Tumor Formation ◽

Hybrid Cells ◽

Mesenchymal Stroma

Cellular communication within the tumor microenvironment enables important interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem-like cells (MSC). These interactions were monitored in vivo following co-injection of GFP-labeled human MSC together with mcherry-labeled MDA-MB-231 breast cancer cells in NODscid mice. Within 14 days of tumor development the number of initially co-injected MSC had significantly declined and spontaneous formation of breast cancer/MSC hybrid cells was observed by the appearance of double fluorescing cells. This in vivo fusion displayed a rare event and occurred in less than 0.5% of the tumor cell population. Similar findings were observed in a parallel in vitro co-culture. Characterization of the new cell fusion products obtained after two consecutive flow cytometry cell sorting and single cell cloning revealed two populations, termed MDA-hyb3 and MDA-hyb4. The breast cancer fusion cells expressed both, GFP and mcherry and displayed more characteristics of the MDA-MB-231 cells than of the parental MSC. While little if any differences were determined in the proliferative capacity, a significant delay of MDA-hyb3 cells in tumor formation was observed when compared to the parental MDA-MB-231 cells. Moreover, MDA-hyb3 cells developed an altered pattern of distant organ metastases. These findings demonstrated dynamic tumor changes by in vivo and in vitro fusion with the development of new breast cancer hybrid cells carrying altered tumorigenic properties. Consequently, cancer cell fusion contributes to progressively increasing tumor heterogeneity which complicates a therapeutic regimen.

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Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation

Cancers ◽

10.3390/cancers11101432 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1432 ◽

Cited By ~ 13

Author(s):

Ralf Hass ◽

Juliane von der Ohe ◽

Hendrik Ungefroren

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Fusion ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Formation ◽

Metastatic Potential ◽

Cell Types ◽

Resistance Mechanisms ◽

Mesenchymal Transition

Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells’ invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.

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Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

Scientific Reports ◽

10.1038/s41598-019-55145-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Matthew Tegowski ◽

Cheng Fan ◽

Albert S. Baldwin

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Cell Types ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Self Renewal ◽

Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

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Cell death and survival due to cytotoxic exposure modelled as a two-state Ising system

Royal Society Open Science ◽

10.1098/rsos.191578 ◽

2020 ◽

Vol 7 (2) ◽

pp. 191578 ◽

Cited By ~ 1

Author(s):

S. Arbabi Moghadam ◽

V. Rezania ◽

J. A. Tuszynski

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Bystander Effect ◽

Selection Process ◽

Mathematical Formulation ◽

Cancer Cell Lines ◽

Interaction Constant ◽

Cytotoxic Agents ◽

Response To Chemotherapy

Cancer chemotherapy agents are assessed for their therapeutic utility primarily by their ability to cause apoptosis of cancer cells and their potency is given by an IC50 value. Chemotherapy uses both target-specific and systemic-action drugs and drug combinations to treat cancer. It is important to judiciously choose a drug type, its dosage and schedule for optimized drug selection and administration. Consequently, the precise mathematical formulation of cancer cells' response to chemotherapy may assist in the selection process. In this paper, we propose a mathematical description of the cancer cell response to chemotherapeutic agent exposure based on a time-tested physical model of two-state multiple-component systems near criticality. We describe the Ising model methodology and apply it to a diverse panel of cytotoxic drugs administered against numerous cancer cell lines in a dose–response manner. The analysed dataset was generated by the Netherlands Translational Research Center B.V. (Oncolines). This approach allows for an accurate and consistent analysis of cytotoxic agents' effects on cancer cell lines and reveals the presence or absence of the bystander effect through the interaction constant. By calculating the susceptibility function, we see the value of IC50 coinciding with the peak of this measure of the system's sensitivity to external perturbations.

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Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/980658 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Claudia Torricelli ◽

Sara Salvadori ◽

Giuseppe Valacchi ◽

Karel Souček ◽

Eva Slabáková ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Electron Microscopic Examination ◽

Cell Types ◽

Beclin 1 ◽

Electron Microscopic ◽

Alternative Pathways ◽

Light Fluorescence ◽

Mcf 7

Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein. The contribution of autophagy and apoptosis to the cytotoxic effects of Rottlerin was examined by light, fluorescence, and electron microscopic examination and by western blotting analysis of apoptotic and autophagic markers. By comparing caspases-3-deficient (MCF-73def) and caspases-3-transfected MCF-7 cells (MCF-73trans), we found that Rottlerin induced a noncanonical, Bcl-2-, Beclin 1-, Akt-, and ERK-independent autophagic death in the former- and the caspases-mediated apoptosis in the latter, in not starved conditions and in the absence of any other treatment. These findings suggest that Rottlerin could be cytotoxic for different cancer cell types, both apoptosis competent and apoptosis resistant.

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Superoxide Dismutase 1 Regulation of CXCR4-Mediated Signaling in Prostate Cancer Cells is Dependent on Cellular Oxidative State

Cellular Physiology and Biochemistry ◽

10.1159/000438566 ◽

2015 ◽

Vol 37 (6) ◽

pp. 2071-2084 ◽

Cited By ~ 6

Author(s):

Brent Young ◽

Chad Purcell ◽

Yi-Qun Kuang ◽

Nicholle Charette ◽

Denis J. Dupré

Keyword(s):

Prostate Cancer ◽

Superoxide Dismutase ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Metastasis ◽

Direct Interaction ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Cell Types ◽

Intracellular Loop

Background/Aims: CXCL12, acting via one of its G protein-coupled receptors, CXCR4, is a chemoattractant for a broad range of cell types, including several types of cancer cells. Elevated expression of CXCR4, and its ligand CXCL12, play important roles in promoting cancer metastasis. Cancer cells have the potential for rapid and unlimited growth in an area that may have restricted blood supply, as oxidative stress is a common feature of solid tumors. Recent studies have reported that enhanced expression of cytosolic superoxide dismutase (SOD1), a critical enzyme responsible for regulation of superoxide radicals, may increase the aggressive and invasive potential of malignant cells in some cancers. Methods: We used a variety of biochemical approaches and a prostate cancer cell line to study the effects of SOD1 on CXCR4 signaling. Results: Here, we report a direct interaction between SOD1 and CXCR4. We showed that SOD1 interacts directly with the first intracellular loop (ICL1) of CXCR4 and that the CXCL12/CXCR4-mediated regulation of AKT activation, apoptosis and cell migration in prostate cancer (PCa) cells is differentially modulated under normal versus hypoxic conditions when SOD1 is present. Conclusions: This study highlights a potential new regulatory mechanism by which a sensor of the oxidative environment could directly regulate signal transduction of a receptor involved in cancer cell survival and migration.

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