Cell Fusion in Human Cancer: The Dark Matter Hypothesis

Weiler, Julian; Dittmar, Thomas

doi:10.3390/cells8020132

Cited by 47 publications

(61 citation statements)

References 111 publications

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“…Cell fusion is an essential biologic process [44][45][46][47][48] . As PCa cells are fusogenic 28 , spontaneity of the fusogeneity results in dynamic tumor cell heterogeneity 49 , the preponderant driver of cancer progression and metastasis. Fusion incidence rate was estimated to be around 0.25%, which we consider highly eventful, because the fusion could lead to the creation of hybrid progenies, with completely diverged genomic makeup and phenotypic behavior from their parental cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell’s neuroendocrine feature can be acquired through cell-cell fusion during cancer-neural stem cell interaction

Yin

Shi

et al. 2020

Sci Rep

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Advanced and therapy-resistant prostate tumors often display neural or neuroendocrine behavior. We assessed the consequences of prostate cancer cell interaction with neural cells, which are rich in the human prostate and resident of the prostate tumor. In 3-dimensional co-culture with neurospheres, red fluorescent human LNCaP cells formed agglomerates on the neurosphere surface. Upon induced neural differentiation, some red fluorescent cells showed morphology of fully differentiated neural cells, indicating fusion between the cancer and neural stem cells. These fusion hybrids survived for extended times in a quiescent state. A few eventually restarted cell division and propagated to form derivative hybrid progenies. Clones of the hybrid progenies were highly heterogeneous; most had lost prostatic and epithelial markers while some had acquired neural marker expression. These results indicate that cancer cells can fuse with bystander neural cells in the tumor microenvironment; and cancer cell fusion is a direct route to tumor cell heterogeneity.Prostate cancer (PCa) has a multifaceted relationship with the nervous system. PCa progression is often accompanied by neurologic complications 1-3 and loss of neurocognitive function 4,5 . PCa patients with neurologic events have poor quality of life, and patients with intracranial metastases have poor survival 6 . The nervous system seems tropistic to PCa progression, as neural peptides and hormones assist tumor growth and survival 7,8 . The peripheral nervous system may serve as a route for cancer infiltration, since PCa cells have high affinity to neural cells 9 and perineuronal spaces are a thoroughfare for spreading tumor cells 10 .Originating from the epithelial layer of the glandular prostate, PCa cells in clinical progression may acquire neural, endocrine, or neuroendocrine properties [11][12][13] . Neuroendocrinal PCa cells by themselves can secrete neural peptides and hormones promoting growth and survival in the absence of androgen, a mechanism of androgen-independent progression 14,15 . The focal or clustered distribution of neuroendocrine PCa cells in clinical specimens suggests clonal origin 16,17 . Neuroendocrine features in PCa are interpreted to result from transdifferentiation due to lineage plasticity 18 and stem cell properties 19 . Soluble factors in the tumor microenvironment may modulate transdifferentiation by receptor-mediated signal transduction 14 , while additional exogeneous conditions may modulate via epigenetic mechanisms 20 .We have demonstrated that PCa progression and metastasis is driven by cancer cell interaction with bystander resident cells in the tumor microenvironment 21-23 . Bystander neuroendocrine cells 11,12 and innervating autonomic nerves 7,24 are constituents as well. Using 3-dimensional (3-D) co-culture and xenograft tumor models, we found that direct contact with cancer cells converted bystander cells to malignant cells with permanent genomic alterations [25][26][27] . Mechanistically, LNCaP and other human PCa cells were fou...

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Section: Discussionmentioning

confidence: 99%

Cancer cell’s neuroendocrine feature can be acquired through cell-cell fusion during cancer-neural stem cell interaction

Yin

Shi

et al. 2020

Sci Rep

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“…With reference to the xenograft milieu, another study reported the host macrophage invasion and the presence of multinuclear giant cells or foreign body giant cells at the implant site upon the injection of human mesenchymal stem cells with biopolymers in NOD scid mice, thus indicating that severely immunocompromised mice are able to retain a certain level of innate immune responsiveness [78]. On the other hand, cell fusion has been associated with the acquisition of increased metastatic capacity or enhanced drug resistance [79], and the presence of circulating hybrid cells was shown to correlate with the disease stage and patient survival [76]. Overall, we are aware that beside the identification based on morphological criteria although performed by a pathologist experienced in CTC detection in clinical samples, only a molecular characterization of such atypical populations of cells, including leukocytes interacting with CTCs, e.g., with species-specific antibodies and gene expression analyses, would definitely elucidate their nature and confirm the validity of xenograft models for new research lines.…”

Section: Discussionmentioning

confidence: 99%

The Detection and Morphological Analysis of Circulating Tumor and Host Cells in Breast Cancer Xenograft Models

Cleris

Daidone

Fina

et al. 2019

Cells

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Hematogenous dissemination may occur early in breast cancer (BC). Experimental models could clarify mechanisms, but in their development, the heterogeneity of this neoplasia must be considered. Here, we describe circulating tumor cells (CTCs) and the metastatic behavior of several BC cell lines in xenografts. MDA-MB-231, BT-474, MDA-MB-453 and MDA-MB-468 cells were injected at the orthotopic level in immunocompromised mice. CTCs were isolated using a size-based method and identified by cytomorphological criteria. Metastases were detected by COX IV immunohistochemistry. CTCs were detected in 90% of animals in each model. In MDA-MB-231, CTCs were observed after 5 weeks from the injection and step wisely increased at later time points. In animals injected with less aggressive cell lines, the load of single CTCs (mean ± SD CTCs/mL: 1.8 ± 1.3 in BT-474, 122.2 ± 278.5 in MDA-MB-453, 3.4 ± 2.5 in MDA-MB468) and the frequency of CTC clusters (overall 38%) were lower compared to MDA-MB231 (946.9 ± 2882.1; 73%). All models had lung metastases, MDA-MB-453 and MDA-MB468 had ovarian foci too, whereas lymph nodal involvement was observed in MDA-MB231 and MDA-MB-468 only. Interestingly, CTCs showed morphological heterogeneity and were rarely associated to host cells. Orthotopic xenograft of BC cell lines offers valid models of hematogenous dissemination and a possible experimental setting to study CTC-blood microenvironment interactions.

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“…Tumor cell fusions have also been found to occur homotypically with other tumor cells [37,38], but also heterotypically with fibroblasts [14,39], stem cells [40], and myeloid-derived cells [15,28,41]. Different techniques have been developed to induce artificial cellular fusion for experimental purposes.…”

Section: Cell Fusion As a Physiological And Pathological Mechanismmentioning

confidence: 99%

“…Fusion between tumor cells and other cells (homo-and heterotypic) might represent a key process generating genetic heterogeneity required to metastasize and develop therapy resistance [12,19,34,41,65,125,126]. Heterogeneity caused by the fusion of stromal cells with breast tumor cells leads to mixed gene expression profiles, transition to a carcinoma phenotype [56], and likely contributes to abnormal chromosomal ploidy [125].…”

Section: Tumor Cell Fusion Leads To Tumor Heterogeneity and Chemoresimentioning

confidence: 99%

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

Manjunath

Porciani

Mitchem

et al. 2020

IJMS

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Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.

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Cell Fusion in Human Cancer: The Dark Matter Hypothesis

Cited by 47 publications

References 111 publications

Cancer cell’s neuroendocrine feature can be acquired through cell-cell fusion during cancer-neural stem cell interaction

Cancer cell’s neuroendocrine feature can be acquired through cell-cell fusion during cancer-neural stem cell interaction

The Detection and Morphological Analysis of Circulating Tumor and Host Cells in Breast Cancer Xenograft Models

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

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