• cancer cell hybrid
• cancer recurrence
• cell fusion
• macrophages
• metastasis
• oncogenic resistance
• tumour hybrid cell

• Humans
• Neoplasms/pathology
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasm Metastasis
• Cell Fusion
• Animals
• Signal Transduction
• Tumor Microenvironment
• Hybrid Cells

• ADAM10
• ADAM17
• NLR
• PLR
• SIR
• cardiovascular diseases (CVD)
• colorectal cancer (CRC)
• diabetes mellitus type 2 (DMT2)
• inflammation
• proteins

• Humans
• ADAM10 Protein/metabolism
• ADAM10 Protein/blood
• Colorectal Neoplasms/blood
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/surgery
• Colorectal Neoplasms/pathology
• ADAM17 Protein/metabolism
• ADAM17 Protein/blood
• Male
• Female
• Aged
• Middle Aged
• Membrane Proteins/blood
• Membrane Proteins/metabolism
• Amyloid Precursor Protein Secretases/metabolism
• Amyloid Precursor Protein Secretases/blood
• Inflammation/blood
• Inflammation/metabolism
• Neutrophils/metabolism
• Blood Platelets/metabolism
• Lymphocytes/metabolism
• Aged, 80 and over
• Adult

• PCN-1-106/K/1/Z and BNW-1-067/K/3/2 Medical University of Silesia

• CP: Cancer
• CP: Cell biology
• adenoid cystic carcinoma
• cell fusion
• fibroblasts
• mitochondrial dysfunction
• mitochondrial transfer

• Humans
• Carcinoma, Adenoid Cystic/metabolism
• Carcinoma, Adenoid Cystic/pathology
• Mitochondria/metabolism
• Animals
• Mice
• Cell Line, Tumor
• Cell Fusion
• Epithelial-Mesenchymal Transition
• Fibroblasts/metabolism
• Tumor Microenvironment

• CD81
• colon cancer
• gene promoter
• transcript
• transcriptome

• Humans
• RNA, Long Noncoding/genetics
• Colonic Neoplasms/genetics
• Colonic Neoplasms/pathology
• Gene Expression Profiling
• Signal Transduction
• Tetraspanin 28/genetics
• Tetraspanin 28/metabolism

• #6052315 Science Fund of the Republic of Serbia

• breast cancer
• circulating tumor cells
• heterogeneity
• single-cell sequencing
• tumor hybrid cells

CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.

• cancer
• cancer stem/initiating cells
• cell-cell fusion

• cancer
• cell fusion
• drug resistance
• metastasis
• tumor hybrid cell

• G protein-coupled receptor
• Gα12
• Gα13
• cell pathophysiology
• diseases

• oncogenes
• cell signalling

• Animals
• GTP-Binding Protein alpha Subunits, G12-G13/genetics
• Humans
• Mice
• Neoplasms/genetics
• Oncogenes/genetics
• Signal Transduction

• aneuploidy
• cancer stem/initiating cell
• cell fusion
• gene transfer
• hybrid cell formation
• mesenchymal stroma-/stem-like cells
• post-hybrid selection process
• tumor plasticity

Cell fusion as a fundamental biological process is required for various physiological processes, including fertilization, placentation, myogenesis, osteoclastogenesis, and wound healing/tissue regeneration. However, cell fusion is also observed during pathophysiological processes like tumor development. Mesenchymal stroma/stem-like cells (MSC) which play an important role within the tumor microenvironment like other cell types such as macrophages can closely interact and hybridize with cancer cells. The formation of cancer hybrid cells can involve various different mechanisms whereby the genomic parts of the hybrid cells require rearrangement to form a new functional hybrid cell. The fusion of cancer cells with neighboring cell types may represent an important mechanism during tumor development since cancer hybrid cells are detectable in various tumor tissues. During this rare event with resulting genomic instability the cancer hybrid cells undergo a post-hybrid selection process (PHSP) to reorganize chromosomes of the two parental nuclei whereby the majority of the hybrid population undergoes cell death. The remaining cancer hybrid cells survive by displaying altered properties within the tumor tissue.

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.

• cell fusion
• heterokaryon-to-synkaryon transition
• horizontal gene transfer/lateral gene transfer
• hybrid cell formation
• mesenchymal stroma-/stem-like cells

Cellular senescence may be a side effect of chemotherapy and other anti-cancer treatments that may promote inflammation and paracrine secondary senescence in healthy tissues. DNMT2/TRDMT1 methyltransferase is implicated in the regulation of cellular lifespan and DNA damage response (DDR). In the present study, the responses to senescence inducing concentrations of doxorubicin and etoposide in different cancer cells with DNMT2/TRDMT1 gene knockout were evaluated, namely changes in the cell cycle, apoptosis, autophagy, interleukin levels, genetic stability and DDR, and 5-mC and NSUN1-6 levels. Moreover, the effect of azacytidine post-treatment was considered. Diverse responses were revealed that was based on type of cancer cells (breast and cervical cancer, osteosarcoma and glioblastoma cells) and anti-cancer drugs. DNMT2/TRDMT1 gene knockout in drug-treated glioblastoma cells resulted in decreased number of apoptotic and senescent cells, IL-8 levels and autophagy, and increased number of necrotic cells, DNA damage and affected DDR compared to drug-treated glioblastoma cells with unmodified levels of DNMT2/TRDMT1. We suggest that DNMT2/TRDMT1 gene knockout in selected experimental settings may potentiate some adverse effects associated with chemotherapy-induced senescence.

• DNMT2/TRDMT1
• anti-cancer drugs
• cancer cells
• chemotherapy-induced senescence

The phenomenon of cancer cell–cell fusion is commonly associated with the origin of more malignant tumor cells exhibiting novel properties, such as increased drug resistance or an enhanced metastatic capacity. However, the whole process of cell–cell fusion is still not well understood and seems to be rather inefficient since only a certain number of (cancer) cells are capable of fusing and only a rather small population of fused tumor hybrids will survive at all. The low survivability of tumor hybrids is attributed to post-fusion processes, which are characterized by the random segregation of mixed parental chromosomes, the induction of aneuploidy and further random chromosomal aberrations and genetic/epigenetic alterations in daughter cells. As post-fusion processes also run in a unique manner in surviving tumor hybrids, the occurrence of novel properties could thus also be a random event, whereby it might be speculated that the tumor microenvironment and its spatial habitats could direct evolving tumor hybrids towards a specific phenotype.

• cancer
• cell–cell fusion
• drug resistance
• metastasis

• Cell Communication
• Cell Fusion
• Chromosome Aberrations
• Humans
• Hybrid Cells/pathology
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Phenotype

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Checkpoint Kinase 2/genetics
• Checkpoint Kinase 2/metabolism
• Citric Acid Cycle
• DNA Damage
• Glycolysis
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Metabolome
• Mice
• Mice, Inbred C57BL
• Mitochondria/metabolism
• Mitochondria/pathology
• Mitosis
• Reactive Oxygen Species/metabolism
• Succinates/metabolism
• Transcriptome

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

• HPV infection
• VSCC
• cell culture
• immunohistochemistry
• prognosis
• siRNA
• tetraspanins

Tumor-initiating cells (TICs) or cancer stem cells are believed to be responsible for gastrointestinal tumor initiation, progression, metastasis, and drug resistance. It is hypothesized that gastrointestinal TICs (giTICs) might originate from cell-cell fusion. Here, we systemically evaluate the evidence that supports or opposes the hypothesis of giTIC generation from cell-cell fusion both in vitro and in vivo. We review giTICs that are capable of initiating tumors in vivo with 5000 or fewer in vivo fused cells. Under this restriction, there is currently little evidence demonstrating that giTICs originate from cell-cell fusion in vivo. However, there are many reports showing that tumor generation in vitro occurs with more than 5000 fused cells. In addition, the mechanisms of giTIC generation via cell-cell fusion are poorly understood, and thus, we propose its potential mechanisms of action. We suggest that future research should focus on giTIC origination from cell-cell fusion in vivo, isolation or enrichment of giTICs that have tumor-initiating capabilities with 5000 or less in vivo fused cells, and further clarification of the underlying mechanisms. Our review of the current advances in our understanding of giTIC origination from cell-cell fusion may have significant implications for the understanding of carcinogenesis and future cancer therapeutic strategies targeting giTICs.

• Gastrointestinal tumor-initiating cell
• Stem cell
• Bone marrow-derived cells
• In vivo
• Cell-cell fusion
• In vitro

• 5-fluorouracil
• colorectal cancer
• resistance mechanism

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.

• Cell fusion
• Hybrid formation
• Polyploidization
• Macrophage
• Cancer progression
• Oncologic treatment resistance

A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century.

• anastasis
• apoptosis
• cancer therapy
• cell fusion
• colony formation assay
• dormancy
• high-throughput assays
• persister
• polyploid giant cancer cells
• senescence

• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Cell Communication/drug effects
• Cell Lineage/genetics
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Drug Resistance, Neoplasm/genetics
• Genetic Heterogeneity
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology

To date, several studies have confirmed that driving forces of the inflammatory tumour microenvironment trigger spontaneous cancer cell fusion. However, less is known about the underlying factors and mechanisms that facilitate inflammation-induced cell fusion of a cancer cell with a normal cell. Recently, we demonstrated that minocycline, a tetracycline antibiotic, successfully inhibited the TNF-α-induced fusion of MDA-MB-435 cancer cells with M13SV1 breast epithelial cells. Here, we investigated how minocycline interferes with the TNF-α induced signal transduction pathway.

A Cre-LoxP recombination system was used to quantify the fusion of MDA-MB-435-pFDR1 cancer cells and M13SV1-Cre breast epithelial cells. The impact of minocycline on the TNF-α signalling pathway was determined by western blotting. The transcriptional activity of NF-κB was characterised by immunocytochemistry, western blot and ChIP analyses. An NF-κB-luciferase reporter assay was indicative of NF-κB activity.

Minocycline treatment successfully inhibited the TNFR1-TRAF2 interaction in both cell types, while minocycline abrogated the phosphorylation of IκBα and NF-κB-p65 to suppress nuclear NF-κB and its promotor activity only in M13SV1-Cre cells, which attenuated the expression of MMP9 and ICAM1. In MDA-MB-435-pFDR1 cells, minocycline increased the activity of NF-κB, leading to greater nuclear accumulation of NF-κB-p65, thus increasing promoter activity to stimulate the expression of ICAM1. Even though TNF-α also activated all MAPKs (ERK1/2, p38 and JNK), minocycline differentially affected these kinases to either inhibit or stimulate their activation. Moreover, SRC activation was analysed as an upstream activator of MAPKs, but no activation by TNF-α was revealed. The addition of several specific inhibitors that block the activation of SRC, MAPKs, AP-1 and NF-κB confirmed that only NF-κB inhibition was successful in inhibiting the TNF-α-induced cell fusion process.

Minocycline is a potent inhibitor in the TNF-α-induced cell fusion process by targeting the NF-κB pathway. Thus, minocycline prevented NF-κB activation and nuclear translocation to abolish the target-gene expression of MMP9 and ICAM1 in M13SV1-Cre cells, resulting in reduced cell fusion frequency.

• Breast cancer
• Cell fusion
• Minocycline
• NF-κB
• TNF-α

• CTCs
• MICs
• MTFs
• macrophage-tumor cell fusions
• metastasis
• metastasis-initiating cells

• Animals
• Cell Fusion
• Humans
• Leukocytes/pathology
• Macrophages/pathology
• Mice
• Neoplasm Metastasis
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplastic Cells, Circulating/pathology

Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance.

Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy γ-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival.

CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells.

Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

• Breast cancer
• CD163
• Radiotherapy
• Treatment resistance
• Tumor-associated macrophages

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment in early stage CRC, chemotherapy is usually given to prolong the overall survival and improve the quality of life for metastatic colorectal cancer (mCRC). But drug resistance is one of the major hurdles of mCRC treatment, and the underlying mechanisms are still largely unknown. In this study, we show that, compared with parental cells, RhoA is up-regulated in irinotecan (CPT-11)-resistant CRC cells. Furthermore, inhibition of RhoA in drug resistant cells, at least partially, rescues the resistance against irinotecan and increases the sensitivity to other chemotherapeutic drug by inhibiting expression of MDR1, MRP1and GSTP1, promotes apoptosis by suppressing the expression of BCL-XL and Bcl-2 and increasing Bax expression, and significantly decreases side population cells. Our results suggest that, in addition to survival, proliferation, migration, adhesion, cell cycle and gene transcription, RhoA is also involved in chemoresistance by regulating the expression of membrane transporter and apoptosis protein in colorectal cancer. They raise an interesting possibility that the expression of RhoA may indicate a poor prognosis due to the high probability to therapy resistance and, on the other hand, inhibition of RhoA activity and function may overcome chemoresistance and improve the effectiveness of clinical treatment of CRC.

• RhoA
• chemoresistance
• colorectal cancer
• irinotecan

CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (P<0.001). CD81 expression had a negative impact on survival (event-free survival, overall survival and relapse-free survival) in univariate (P<0.001) and in multivariate analyses (P=0.003, 0.002 and <0.001, respectively). CD81 has a negative impact on OS in patients with NPM1 mutation (P=0.01) and in patients ELN-favorable (P=0.002). In conclusion, this cell surface marker may be a new prognostic marker for diagnostic risk classification and a potential therapeutic target for drug development in AML.

• CD81
• acute myeloid leukemia
• flow cytometry
• prognosis
• tetraspanin

• GENETIC INSTABILITY
• HEPATOBILIARY CANCER

Cell-cell fusion describes the process by which two cells combine their plasma membranes and become a single cell, possessing and retaining certain genetic information from each parent cell. Here, using a Cre-loxP-based method initially developed to investigate extracellular vesicle targeting, we found that cancer cells spontaneously and rapidly deliver DNA to non-cancer cells in vitro via a cell-cell fusion event. The resulting hybrid cells were aneuploid and possessed enhanced clonal diversity and chemoresistance compared to non-hybrid cancer cells. We also observed cell-cell fusion to occur in vivo between melanoma cells and non-cancer cells of both hematopoietic and non-hematopoietic lineages. These findings suggest that cell-cell fusion occurs during the natural progression of cancer and show that this mechanism has the potential to cause massive genomic alterations that are observed in cancer. Furthermore, these findings somewhat contradict recent publications suggesting that the Cre-loxP method measures only extracellular vesicle-mediated intercellular communication.

• aneuploidy
• cancer heterogeneity
• cell-cell fusion
• chemoresistance
• clonal diversity

Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage:cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy γ-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage:cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence.

• M2-macrophage
• breast cancer
• cell fusion
• radioresistance
• radiotherapy

Toll-like receptors (TLRs) belong to the group of pathogen recognition receptors known to play a crucial role in the innate immune system. In cancer, TLR expression is still debated controversially due to contradictory results reporting that both induction of apoptosis as well as tumor progression could depend on TLR signaling, whereby recent data rather indicate a pro-tumorigenic effect. The biological phenomenon of cell fusion has been associated with cancer progression due to findings revealing that fusion-derived hybrid cells could exhibit properties like an increased metastatogenic capacity and an increased drug resistance. Thus, M13MDA435 hybrid cell lines, which derived from spontaneous fusion events between human M13SV1-EGFP-Neo breast epithelial cells and human MDA-MB-435-Hyg breast cancer cells, were investigated. Cultivation of cells in the presence of the TLR4 ligand LPS potently induced apoptosis in all hybrid clones, but not in parental cells, which was most likely attributed to differential kinetics of the TLR4 signal transduction cascade. Activation of this pathway concomitant with NF-κB nuclear translocation and TNF-α expression was solely observed in hybrid cells. However, induction of LPS mediated apoptosis was not TNF-α dependent since TNF-α neutralization was not correlated to a decreased amount of dead cells. In addition to TNF-α, LPS also caused IFN-β expression in hybrid clones 1 and 3. Interestingly, hybrid clones differ in the mode of LPS induced apoptosis. While neutralization of IFN-β was sufficient to impair the LPS induced apoptosis in M13MDA435-1 and -3 hybrids, the amount of apoptotic M13MDA435-2 and -4 hybrid cells remained unchanged in the presence of neutralizing IFN-β antibodies. In summary, the fusion of non-LPS susceptible parental human breast epithelial cells and human breast cancer cells gave rise to LPS susceptible hybrid cells, which is in view with the cell fusion hypothesis that hybrid cells could exhibit novel properties.

• Apoptosis
• Breast Neoplasms/pathology
• Cell Fusion
• Cell Line, Tumor
• Cell Nucleus/metabolism
• Cell Proliferation
• Disease Progression
• Drug Resistance, Neoplasm
• Enzyme-Linked Immunosorbent Assay
• Epithelial Cells/cytology
• Female
• Humans
• Hybrid Cells/cytology
• Interferon-beta/metabolism
• Ligands
• Lipopolysaccharides
• NF-kappa B/metabolism
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha/metabolism

• Density gradient centrifugation
• Hepatocellular carcinoma cells
• Human hepatic stellate cells
• Tetraspanin -enriched microdomains
• Tetraspanins
• Thin layer chromatography

• 1-Phosphatidylinositol 4-Kinase/metabolism
• Cell Line, Tumor
• Cells, Cultured
• Hepatic Stellate Cells
• Hepatocytes/metabolism
• Humans
• Immunoprecipitation
• Membrane Microdomains/metabolism
• Protein Binding
• Tetraspanins/metabolism

• aneuploidy
• cancer
• cell fusion
• chromothripsis
• genomic instability
• mutations
• mutator phenotype
• tissue regeneration

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacokinetics
• Delayed-Action Preparations
• Drug Carriers/administration & dosage
• Drug Carriers/chemistry
• Drug Carriers/pharmacokinetics
• Fluorescent Dyes/administration & dosage
• Fluorescent Dyes/chemistry
• Fluorescent Dyes/pharmacokinetics
• HCT116 Cells
• Humans
• Liver Neoplasms, Experimental/diagnosis
• Liver Neoplasms, Experimental/drug therapy
• Liver Neoplasms, Experimental/metabolism
• Male
• Mice
• Mice, Nude
• Nanostructures/administration & dosage
• Nanostructures/chemistry
• Polymers/administration & dosage
• Polymers/chemistry
• Polymers/pharmacokinetics

• Breast cancer
• Cell fusion
• Cre-LoxP recombination
• Flow cytometry

• Blotting, Western
• Breast Neoplasms/physiopathology
• Cell Fusion/methods
• Cell Hypoxia/physiology
• Cell Line, Tumor
• Female
• Flow Cytometry
• Genetic Vectors/genetics
• Genetic Vectors/metabolism
• Green Fluorescent Proteins/metabolism
• Humans
• Integrases
• Mammary Glands, Human/physiology
• Microscopy, Electron, Scanning
• Tumor Necrosis Factor-alpha/metabolism

• Development
• EMT
• Fibrosis
• Metastasis
• TM4SF5

There are 33 human tetraspanin proteins, emerging as key players in malignancy, the immune system, fertilization, cellular signaling, adhesion, morphology, motility, proliferation, and tumor invasion. CD9, a member of the tetraspanin family, associates with and influences a variety of cell-surface molecules. Through these interactions, CD9 modifies multiple cellular events, including adhesion, migration, proliferation, and survival. CD9 is therefore considered to play a role in several stages during cancer development. Reduced CD9 expression is generally related to venous vessel invasion and metastasis as well as poor prognosis. We found that treatment of mice bearing human gastric cancer cells with anti-CD9 antibody successfully inhibited tumor progression via antiproliferative, proapoptotic, and antiangiogenic effects, strongly indicating that CD9 is a possible therapeutic target in patients with gastric cancer. Here, we describe the possibility of CD9 manipulation as a novel therapeutic strategy in gastric cancer, which still shows poor prognosis.

• CD9
• Tetraspanin
• Gastric cancer
• Tumorigenicity
• Therapeutic target

• Animals
• Antibodies/adverse effects
• Antibodies/therapeutic use
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Humans
• Molecular Targeted Therapy
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/immunology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tetraspanin 29/antagonists & inhibitors
• Tetraspanin 29/immunology
• Tetraspanin 29/metabolism
• Treatment Outcome

The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC) morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes. Upon knocking down CD9, the cells developed an abnormally small and rounded morphology. We determined that this morphological change was due to a lack of typical parallel actin arrangement. We also found similar total RhoA but decreased GTP-bound (active) RhoA levels in CD9 deficient cells. As a result, cells lacking a full complement of CD9 were less contractile than their control treated counterparts. Upon restoration of RhoA activity in the CD9 deficient cells, the phenotype was reversed and cell contraction was restored. Conversely, inhibition of RhoA activity in the control cells mimicked the CD9-deficient cell phenotype. Thus, alteration in CD9 expression was sufficient to profoundly disrupt cellular actin arrangement and endogenous cell contraction by interfering with RhoA signaling. This study provides insight into how CD9 may regulate previously described vascular smooth muscle cell pathophysiology.

• trastuzumab
• resistance
• adam10
• her2
• survival

• ADAM Proteins/biosynthesis
• ADAM Proteins/genetics
• ADAM Proteins/metabolism
• ADAM10 Protein
• Amyloid Precursor Protein Secretases/biosynthesis
• Amyloid Precursor Protein Secretases/genetics
• Amyloid Precursor Protein Secretases/metabolism
• Animals
• Antibodies, Monoclonal, Humanized/pharmacology
• Antineoplastic Agents/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/enzymology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Proliferation/physiology
• Drug Resistance, Neoplasm
• Female
• Gene Knockdown Techniques
• Humans
• Membrane Proteins/biosynthesis
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice
• Receptor, ErbB-2/metabolism
• Trastuzumab
• Xenograft Model Antitumor Assays

• 11359 Cancer Research UK
• 16464 Cancer Research UK

• Cell fusion
• Chemoresistance
• Endothelial cell
• Nuclear fusion
• Oral cancer
• RFP
• eGFP

• Cancer heterogeneity
• Cancer progression
• Hepatocellular carcinoma
• Metastasis
• Tetraspanins

• ADAM10
• diagnostic marker
• hepatocellular carcinoma
• tumour progression