Cytoplasmic SIRT1 enhances the stemness of polyploid giant cancer cells by promoting β-catenin protein stability and nuclear accumulation in ovarian carcinoma upon neoadjuvant chemotherapy.

Over a century ago, it was found that cancer cells often have extra chromosomes; that is, normal human cells contain 46 chromosomes, whereas cancer cells contain abnormal numbers of chromosomes with cell-to-cell variability. Polyploid giant cancer cells (PGCCs) refer to a special subpopulation of cancer cells with giant and multinuclei and contribute to solid tumor heterogeneity. PGCCs differ from normal cells and even other cancer cells in cell size, morphology, proliferation pattern, expression of cell differentiation markers, and chromosome numbers and contribute to tumor formation and chemoradioresistance. The shape of PGCC nuclei is usually irregular and the size is at least three to five times larger than those of regular diploid cancer cells. PGCCs are the key contributor to the heterogeneity of human solid cancers and chromosome structural abnormalities, such as inversions, deletions, duplications, and translocations. Mechanistically, PGCCs could be formed through end reduplication or cell fusion, reverting to regular cancer cells through splitting, budding, or burst-like mechanisms. PGCCs are divided asymmetrically and cycled slowly to form a dynamic population. However, these giant cells can also revert to regular-sized cancer cells through a reductive division, named as depolyploidization. Asymmetric cell division of giant cancer cells by meiosis-like depolyploidization had been previously proposed to explain the unexpected life cycle of these cells. In this special issue, D. Zhang et al. reported the asymmetric cell division in polyploid giant cancer cells and low eukaryotic cells and revealed the similarities in the budding process between yeast and PGCCs. This mechanism of PGCCs initialed the daughter cell generation which has also been reported in the normal growth of skeletal muscle and osteoclasts and in cells infected by virus or in vitro cell culture. Moreover, PGCCs were able to express certain normal and cancer stem cell markers and differentiate into the adipose tissue, cartilage, and bone. Single PGCC was able to form cancer spheroids in vitro and generate tumor xenograft in immunodeficient mice, indicating that these PGCCs had remarkable biologic features of cancer stem cells. Furthermore, PGCCs are able to generate erythrocytes in vitro and in vivo besides their cancer stem cell properties. The difference of erythrocytes generated by bone marrow and PGCCs is the different forms of hemoglobin (see below). In human body, erythrocytes are produced in the bone marrow with a process known as hematopoiesis. The bone marrow stroma contains mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), which give rise to erythrocytes, leukocytes, and platelets. In adults, bone marrow is generally considered the main source of erythrocytes. However, PGCCs have an ability to generate erythrocytes in vitro and in vivo. During cancer development, tumor cells undergo avascular growth. However, after a tumor mass reached a certain size, vasculogenic mimicry (VM) will connect with endothelium dependent vessels to obtain sufficient blood and oxygen supply to support further growth of tumor cells and support tumor invasion and metastasis. Accumulating evidence has demonstrated that different types of cancer utilize VM to form a blood supply network to support their growth, invasion, and metastasis and, clinically, such a tumor is usually associated with poor prognosis. However, the source of erythrocytes in VM remains unclear. PGCCs can be induced by treatment of cancer cells with cobalt chloride (a hypoxia mimic) in vitro and hypoxia will increase self-renewal of cancer stem cells and promote the stem cell-like phenotype besides induction of PGCCs formation. Moreover, hypoxia also promotes the formation of vasculogenic mimicry (VM). B. Sun et al. showed that hypoxia inducible factor-1α plays an important role in the VM formation, while L. Zhang et al. provided the evidence that erythroid cells were localized in the cytoplasm of or around the PGCCs in serous ovarian carcinoma tissues and cancer cells in the VM structures and that these erythroid cells expressed hemoglobin-β/γ/e/δ and hemoglobin-ζ detected by immunostaining. Thus, these VM structures can be formed by PGCCs or other cancer cells and their newly generated fetal erythrocytes with high O2 binding affinity. In addition, in this special issue, W. Wang et al. and L. Yao et al. demonstrated that epithelial-mesenchymal transition and Wnt signaling pathway could regulate the VM formation. Thus, elucidation of the molecular mechanisms of PGCC and VM formation could provide a novel insight into research in embryology, stem cells, and tumorigenesis. Identification of the PGCCs and tumor-derived erythrocytes could be a survival mechanism in hypoxia and targeting of PGCCs might be further developed as a potential therapeutic strategy for human cancers. Research focus on VM-targeted therapies could include dendritic cell vaccine and cytokine-induced killer cell therapy to conquer the recurrence and metastasis of aggressive cancers. Shiwu Zhang Xiaochun Xu Siwei Zhu Jun Liu

Introduction/Objective Polyploid giant cancer cells (PGCCs) are large, mono- or multinucleated tumor cells implicated in cancer initiation, metastasis, and therapy resistance. First described in 1914, PGCCs have been observed across various solid tumors, including breast, prostate, and ovarian cancers. They are believed to arise through endoreplication in response to environmental stressors such as hypoxia, inflammation, and anticancer therapies. Despite their clinical relevance, PGCCs remain underrecognized due to their morphological heterogeneity and the absence of standardized detection methods. Their identification is further complicated by the lack of computational tools capable of reliably detecting and characterizing them in tumor samples. In ovarian cancer, particularly high-grade serous ovarian carcinoma (HGSOC), PGCCs may contribute to treatment failure and poor prognosis. This study aimed to address this gap by integrating immunohistochemistry (IHC) with digital pathology to develop a reproducible method for PGCC detection. Using membrane-targeted markers, we sought to delineate tumor cell boundaries and identify PGCCs in formalin-fixed paraffin-embedded (FFPE) samples. The study also evaluated the association between PGCC burden and clinical, histopathological, and molecular features in ovarian cancer. By establishing a standardized detection method, this research aims to enhance our understanding of PGCCs and their potential prognostic value in ovarian cancer management. Methods/Case Report This study evaluated four membrane markers—EpCAM, Na+/K+ ATPase, cadherins, and PMCA1—via immunohistochemistry (IHC) in 40 aggressive tumor cases, including high-grade serous ovarian carcinoma (HGSOC), glioblastoma, triple-negative breast cancer, and pancreatic adenocarcinoma. Marker performance was assessed based on specificity, intensity, uniformity, reproducibility, and compatibility with other IHC reagents. EpCAM was selected for its superior membrane delineation and applied to 26 FFPE ovarian cancer samples collected between 2015 and 2022. Slides were digitized using the Aperio ScanScope CS System and analyzed with Aperio ImageScope software. PGCCs were identified and scored (0–3) using both digital pathology and conventional light microscopy. EpCAM staining intensity was evaluated visually and digitally, and differences were statistically analyzed using the Wilcoxon signed-rank test. Clinical data (age, stage, treatment type), histological parameters (mitotic index, morphology), and molecular findings (BRCA, TP53, ATM, CHEK2) were collected. TP53 mutations were assessed via next-generation sequencing (NGS) in 25 patients. Treatment sequence (primary debulking vs. neoadjuvant chemotherapy) and survival outcomes were also analyzed. The study aimed to correlate PGCC burden with clinical and molecular features to assess its prognostic significance. All procedures were conducted under institutional review board approval and followed standard pathology protocols. Results All four membrane markers delineated tumor cell membranes effectively, enabling PGCC identification. EpCAM, Na+/K+ ATPase, and PMCA1 outperformed cadherins in staining quality. EpCAM was selected for further analysis due to its superior performance. In the 26 HGSOC cases, EpCAM staining revealed significant intra- and intertumoral heterogeneity. PGCCs were more frequently identified using digital pathology than visual assessment, with statistically significant differences in scoring (Wilcoxon signed-rank test, p < 0.05). Patients with low PGCC scores (0–1) had a longer median overall survival (62 months) compared to those with high scores (2–3; 39 months), though this difference did not reach statistical significance (Mann–Whitney U test: p = 0.066). At the time of analysis, 50% of low-score patients were alive versus 17% in the high-score group (Fisher’s Exact Test: p = 0.149). All sequenced tumors harbored TP53 mutations, including frameshifts, missense substitutions, and deletions, with strong concordance between mutation type and p53 IHC patterns. BRCA mutations were present in ∼18% of cases; ATM and CHEK2 mutations were less frequent. Patients who underwent primary debulking surgery showed a trend toward improved survival compared to those receiving neoadjuvant chemotherapy, although this was not statistically significant (p = 0.096). Conclusion This study establishes a reproducible method for detecting polyploid giant cancer cells (PGCCs) in high-grade serous ovarian carcinoma using EpCAM-based immunohistochemistry and digital pathology. Digital analysis proved more sensitive than visual assessment, enabling consistent identification of PGCCs and revealing a trend toward poorer survival in patients with higher PGCC scores. Although not statistically significant, this trend suggests a potential prognostic role for PGCCs. The universal presence of TP53 mutations and the observed variability in treatment outcomes underscore the biological and clinical complexity of HGSOC. These findings support further investigation into PGCCs as prognostic biomarkers and therapeutic targets in ovarian cancer.

BackgroundGenomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity.MethodsCAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle.ResultsAutophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52–84% inhibition).ConclusionsWhile the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.

Our recent perplexing findings that polyploid giant cancer cells (PGCCs) acquired embryonic-like stemness and were capable of tumor initiation raised two important unanswered questions: how do PGCCs acquire such stemness, and to which stage of normal development do PGCCs correspond. Intriguingly, formation of giant cells due to failed mitosis/cytokinesis is common in the blastomere stage of the preimplantation embryo. However, the relationship between PGCCs and giant blastomeres has never been studied. Here, we tracked the fate of single PGCCs following paclitaxel-induced mitotic failure. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the blastomere, polyploid blastomere, compaction, morula and blastocyst-like stages by light, scanning electron or three-dimensional confocal scanning microscopy. Formation of PGCCs was associated with activation of senescence, while budding of daughter cells was associated with senescence escape. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2 and SSEA1 and lacked expression of Xist. PGCCs acquired mesenchymal phenotype and were capable of differentiation into all three germ layers in vitro. The embryonic-like stemness of PGCCs was associated with nuclear accumulation of YAP, a key mediator of the Hippo pathway. Spheroids derived from single PGCCs grew into a wide spectrum of human neoplasms, including germ cell tumors, high-grade and low-grade carcinomas and benign tissues. Daughter cells derived from PGCCs showed attenuated capacity for invasion and increased resistance to paclitaxel. We also observed formation of PGCCs and dedifferentiation in ovarian cancer specimens from patients treated with chemotherapy. Taken together, our findings demonstrate that PGCCs represent somatic equivalents of blastomeres, the most primitive cancer stem cells reported to date. Thus, our studies reveal an evolutionarily conserved archaic embryonic program in somatic cells that can be de-repressed for oncogenesis. Our work offers a new paradigm for cancer origin and disease relapse.

We have recently shown that polyploid giant cancer cells (PGCCs) are capable of tumor initiation and acquisition of embryonic-like stemness and thus represent a novel type of cancer stem cells. However, two important questions remain to be answered from this surprising finding: (1) how PGCCs acquire such stemness; (2) on which stage of normal development PGCCs correspond to. Here, we tracked the fate of single PGCCs induced via mitotic failure by paclitaxel. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the polyploid blastomere, compaction, morula, and blastocyst-like stages by scanning electron microscopy. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2, and SSEA-1 and lacked expression of Xist. PGCCs also showed time-dependent activation of expression of the germ layer-specific markers alpha-fetoprotein, smooth muscle actin, and β3-tubulin and were capable of redifferentiation into three germ layers in vitro. PGCCs-derived daughter cells showed attenuated invasive ability and increased resistance to paclitaxel. PGCCs-derived spheroids grew into a wide spectrum of human neoplasms, including malignant dysgerminoma and embryonic carcinoma, poorly differentiated or well-differentiated carcinomas, and benign squamous tissue. We also observed PGCCs in ovarian cancer from patients treated with chemotherapy. Thus, our data demonstrated that PGCCs acquired novel cancer stem cell properties and capability to redifferentiate into different tumors including the germ cell tumors, which are at the topmost developmental hierarchy. Our studies, for the first time, link PGCCs to the polyploid blastomere-like cancer stem cells and thus offer a new paradigm for the origin of cancer. Citation Format: Na Niu, Jinsong Liu. Dedifferentiation into polyploid blastomere-like cancer stem cells via formation of polyploid giant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 924. doi:10.1158/1538-7445.AM2017-924

Purpose: We previously reported that polyploid giant cancer cells (PGCCs) induced by cobalt chloride (CoCl2) exhibit cancer stem cell properties. Daughter cells generated by PGCCs possess epithelial mesenchymal transition (EMT) phenotype changes and EMT plays an important role in cancer development and progression. This study investigated the characteristics of PGCCs from LoVo and HCT116 induced by CoCl2 and the clinicopathological significances of PGCCs in colorectal cancer (CRC).Materials and Methods: Western blotting and immunocytochemical staining were used to compare the expression levels of EMT-related proteins between PGCCs with budding daughter cells and the control cells. In addition, tissue samples were collected from 159 patients with CRC for analysis of PGCCs, vasculogenic mimicry (VM), and single stromal PGCCs with budding, as well as immunohistochemical staining for cathepsin B, vimentin, and hemoglobin A.Results: Single PGCCs induced by CoCl2 formed spheroids in vitro. Poorly differentiated CRCs showed the highest numbers of PGCCs and VM, and expression of cathepsin B. There was greater expression of EMT-related proteins in PGCCs with budding daughter cells than in control cells. The expression of vimentin located in PGCC nuclei. Single stomal PGCCs with budding were detected in 27.45% of well differentiated, 50% of moderately differentiated, and 90.20% of poorly differentiated CRC samples. PGCCs can generate erythroid cells that express delta-hemoglobin to form VM. Erythroid cells generated by PGCCs were positive for hemoglobin A immunocytochemical staining.Conclusion: PGCCs from LoVo and HCT116 treated by CoCl2 exhibited cancer stem cell properties. The number of PGCCs and VM were associated with CRC differentiation and daughter cells budded from PGCCs may promote the lymph node metastasis via expression of EMT-related proteins. PGCCs and their newly generated erythroid cells form VM structures.

Are polyploid giant cancer cells in high grade serous carcinoma of the ovary blastomere-like cancer stem cells?

Polyploid giant cancer cell characterization: New frontiers in predicting response to chemotherapy in breast cancer

Polyploid giant cancer cells (PGCCs) are a morphologically distinct subgroup of human tumor cells with increased nuclear size or multiple nuclei, but they are generally considered unimportant because they are presumed to be nondividing and thus nonviable. We have recently shown that these large cancer cells are not only viable but also can divide asymmetrically and yield progeny cancer cells with cancer stem-like properties via budding division. To further understand the molecular events involved in the regulation of PGCCs and the generation of their progeny cancer cells, we comparatively analyzed the proteomic profiles of PGCCs, PGCCs with budding daughter cells, and regular control cancer cells from the HEY and SKOv3 human ovarian cancer cell lines with and without CoCl2. We used a high-throughput iTRAQ-based proteomic methodology coupled with liquid chromatography-electrospray ionization tandem mass spectroscopy to determine the differentiated regulated proteins. We performed Western blotting and immunohistochemical analyses to validate the differences in the expression patterns of a variety of proteins between PGCCs or budding PGCCs and regular cancer cells identified by iTRAQ approach and also a selected group of proteins from the literature. The differentially regulated proteins included proteins involved in response to hypoxia, stem cell generation, chromatin remodeling, cell-cycle regulation, and invasion and metastasis. In particular, we found that HIF-1alpha and its known target STC1 are upregulated in PGCCs. In addition, we found that a panel of stem cell-regulating factors and epithelial-to-mesenchymal transition regulatory transcription factors were upregulated in budding PGCCs, whereas expression of the histone 1 family of nucleosomal linker proteins was consistently lower in PGCCs than in control cells. Thus, proteomic expression patterns provide valuable insight into the underlying mechanisms of PGCC formation and the relationship between PGCCs and cancer stem cells in patients with ovarian cancers.

Purpose: Cancer stem cells (CSCs) are the evil source of tumor metastasis and recurrence. Polyploid giant cancer cells (PGCCs) that exhibit the characteristics of CSCs produced daughter cells via asymmetric division. The molecular mechanisms of daughter cells derived from PGCCs with high migration, invasion, and proliferation abilities in colorectal cancer (CRC) are explored in this paper based on the bioinformatics analysis.Materials and Methods: We characterized the expression of CSC-related genes in CRCs by analyzing the mRNAsi of The Cancer Genome Atlas and survival time. Weighted gene co-expression network analysis was performed to identify the modules of the hub and key genes. The migration, invasion, and proliferation abilities of cells, the expression of epithelial-mesenchymal transition (EMT)-related proteins and polo-like kinase 4 (PLK4) were compared in LoVo and Hct116 cells with and without bufalin treatment. In addition, the expression and subcellular location of cell division cycle 25C (CDC25C) in cells before and after PLK4 knockdown were assessed.Results: Eight hub genes were screened out and positively association with mRNAsi in CRCs based on bioinformatic analysis. Among them, checkpoint Kinase-1 (CHEK1), budding uninhibited by benzimidazoles 1 Homolog Beta (BUB1B) and PLK4 were closely associated with the prognosis of CRC patients. Bufalin could induce the formation of PGCCs in LoVo and Hct116 cell lines. PLK4 was overexpressed in PGCCs with progeny cells and progeny cells derived from PGCCs had strong migration and invasion abilities by expressing epithelial-mesenchymal transition (EMT)-related proteins. PLK4 could interact with CDC25C and promote CDC25C phosphorylation which was associated with the formation of PGCCs. Decreasing CDC25C expression in both LoVo and Hct116 PGCCs with progeny cells, while levels of pCDC25C-ser216 and pCDC25C-ser198 were increased in LoVo and decreased in Hct116 PGCCs with progeny cells. pCDC25C-ser216 located in the cytoplasm and pCDC25C-ser198 located in the nucleus in cells after bufalin treatment. Furthermore, expression of CDC25C, pCDC25C-ser216, and pCDC25C-ser198 was downregulated after PLK4 knockdown. Furthermore, the expression level of PLK4 was associated with differentiated degree, and lymph node metastasis in human CRC tissues.Conclusion: PLK4 contributes to the formation of PGCCs by regulating the expression of CDC25C and is associated with the expression and subcellular location of CDC25C, pCDC25C-ser216 and pCDC25C-ser198.

Whole genomic duplications (WGD) have been reported in 37% to 56% of high-grade cancers. WGD leads to formation of polyploid giant cancer cells (PGCCs) with salient and atypical nuclear morphology noted by light microscopy. However, PGCCs are generally considered nonviable due to their inability to execute mitosis. We have recently reported that PGCCs are capable of generating mitosis-competent progeny cells via primitive amitotic division including budding, splitting, and burst. We have further demonstrated that PGCCs are part of the process of somatic reprogramming named the giant cell life cycle composed of four distinct but overlapping phases including initiation, self-renewal, termination, and stability. The giant cell life cycle resets the somatic cell from the mitotic cycle to stress-induced endoreplication cell cycle via WGD to form PGCCs. The PGCCs activate endogenous embryonic factors for the reprogramming, which leads to the birth of drug-resistant cells by clonal selection from newly generated heterogeneous cancer stem cells. However, the underlying genetic and epigenetic mechanisms during WGD remain unclear. By mapping DNA methylation and whole-genome sequencing, monitoring the telomere dynamics, and tracking the cellular and nuclear morphology using microscopic time-lapse imaging observations during the time course of giant cell life cycle, we hereby provide new evidence that the daughters cells derived from PGCCs have massive alterations at the whole-genome and epigenome levels. The reprogrammed resistant daughter cells are achieved, at least in part, by genomic instability via shortened telomeres. Targeting PGCCs and promoting their differentiation during the course of giant cell life cycle may represent a novel approach to intercept drug resistance. Citation Format: Na Niu, Xiaoran Li, Jun Yao, Anil Sood, Jinsong Liu. Polyploid giant cancer cells lead to evolution of drug resistance in high-grade ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A17.

Polyploid giant cancer cells (PGCCs) are an important feature of cellular atypia, the detailed mechanisms of their formation and function remain unclear. PGCCs were previously thought to be derived from repeated mitosis/cytokinesis failure, with no intrinsic ability to proliferate and divide. However, recently, PGCCs have been confirmed to have cancer stem cell (CSC)-like characteristics, and generate progeny cells through asymmetric division, which express epithelial-mesenchymal transition-related markers to promote invasion and migration. The formation of PGCCs can be attributed to multiple stimulating factors, including hypoxia, chemotherapeutic reagents, and radiation, can induce the formation of PGCCs, by regulating the cell cycle and cell fusion-related protein expression. The properties of CSCs suggest that PGCCs can be induced to differentiate into non-tumor cells, and produce erythrocytes composed of embryonic hemoglobin, which have a high affinity for oxygen, and thereby allow PGCCs survival from the severe hypoxia. The number of PGCCs is associated with metastasis, chemoradiotherapy resistance, and recurrence of malignant tumors. Targeting relevant proteins or signaling pathways related with the formation and transdifferentiation of adipose tissue and cartilage in PGCCs may provide new strategies for solid tumor therapy.

Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

BackgroundWe previously reported that polyploid giant cancer cells (PGCCs) exhibit cancer stem cell properties and express cell cycle-related proteins. HEY PGCCs induced by cobalt chloride generated daughter cells and the daughter cells had a strong migratory and invasive ability. This study is to compare the expression of cyclin E, S-phase kinase-associated protein 2 (SKP2), and stathmin between PGCCs with budding and control HEY cells, and determine the clinicopathological significance of cell cycle-related protein expression in ovarian tumors.MethodsWe used western blot and immunocytochemical staining to compare the expression levels of cyclin E, SKP2 and stathmin between PGCC with budding daughter cells and control HEY cells. In addition, immunohistochemical staining for cyclin E, SKP2 and stathmin was performed on a total of 80 paraffin-embedded serous ovarian tumor tissue samples. The samples included 21 cases of primary high-grade carcinoma (group I) and their metastatic tumors (group II), 26 cases of primary low-grade carcinoma without metastasis (group III), and 12 cases of serous borderline cystadenoma (group IV).ResultsSingle PGCC with budding in the stroma showed high correlation with the metastasis of ovarian carcinoma. Group I had a significantly higher number of single PGCCs with budding in the stroma than group III (85.71% [18/21] vs. 23.08% [6/26] cases; χ2 = 18.240, P = 0.000). The expression of cyclin E, SKP2, and stathmin was compared among the four groups. The expression levels of cyclin E, SKP2, and stathmin increased with the malignant grade of ovarian tumors and group II had the highest expression levels. The expression of cyclin E (χ2 = 17.985, P = 0.000), SKP2 (χ2 = 12.384, P = 0.000), and stathmin (χ2 = 20.226, P = 0.000) was significantly different among the 4 groups.ConclusionsThese data suggest that the cell cycle-related proteins cyclin E, SKP2, and stathmin may be valuable biomarkers to evaluate the metastasis in patients with ovarian serous carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-576) contains supplementary material, which is available to authorized users.

To understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs following treatment with paclitaxel in ovarian cancer cells. An acute activation of IL-6 dominated senescence-associated secretory phenotype lasted 2–3 weeks and declined during the termination phase of polyploidy. IL-6 activates embryonic stemness during the initiation of PGCCs and can reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) via increased collagen synthesis, activation of VEGF expression, and enrichment of CAFs and the GPR77 + /CD10 + fibroblast subpopulation. Blocking the IL-6 feedback loop with tocilizumab or apigenin prevented PGCC formation, attenuated embryonic stemness and the CAF phenotype, and inhibited tumor growth in a patient-derived xenograft high-grade serous ovarian carcinoma model. Thus, IL-6 derived by PGCCs is capable of reprogramming both cancer and stromal cells and contributes to the evolution and remodeling of cancer. Targeting IL-6 in PGCCs may represent a novel approach to combating drug resistance.