Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer

2019 ◽  
Vol 19 (5) ◽  
pp. 360-367 ◽  
Author(s):  
Junsong Chen ◽  
Na Niu ◽  
Jing Zhang ◽  
Lisha Qi ◽  
Weiwei Shen ◽  
...  

Polyploidy is associated with increased cell size and is commonly found in a subset of adult organs and blastomere stage of the human embryo. The polyploidy is formed through endoreplication or cell fusion to support the specific need of development including earliest embryogenesis. Recent data demonstrated that Polyploid Giant Cancer Cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy.

2021 ◽  
Vol 17 (1) ◽  
pp. 104-120
Author(s):  
N. Ivanenko

Relevance. Treatment of solid tumors and biofilm-derived infections face a common problem: drugs often fail to reach and kill cancer cells and microbial pathogens because of local microenvironment heterogeneities. There are remarkable challenges for current and prospective anticancer and antibiofilm agents to target and maintain activity in the microenvironments where cancer cells and microbial pathogens survive and cause the onset of disease. Bacterial infections in cancer formation will increase in the coming years. Collection of approaches such as ROS modulation in cells, the tumor is promoted by microbe’s inflammation can be a strategy to target cancer and bacteria. Besides that, bacteria may take the advantage of oxygen tension and permissive carbon sources, therefore the tumor microenvironment (TM) becomes a potential refuge for bacteria. It is noteworthy that the relationship between cancer and bacteria is intertwined. Objective: To analyze similarities between biofilm and tumor milieu that is produced against stress conditions and heterogeneous microenvironment for a combination of approaches the bacteriotherapy with chemotherapy which can help in defeating the tumor heterogeneity accompanied with malignancy, drug-resistance, and metastasis. Method: An analytical review of the literature on keywords from the scientometric databases PubMed, Wiley. Results: Bacteria evade antimicrobial treatment is mainly due to persistence that has become dormant during the stationary phase and tolerance. Drug-tolerant persisters and cellular dormancy are crucial in the development of cancer, especially in understanding the development of metastases as a late relapse. Biofilms are formed by groups of cells in different states, growing or non-growing and metabolically active or inactive in variable fractions, depending on maturity and on chemical gradients (O2 and nutrients) of the biofilms producing physiological heterogeneity. Heterogeneity in the microenvironment of cancer can be described as a non-cell autonomous driver of cancer cell diversity; in a highly diverse microenvironment, different cellular phenotypes may be selected for or against in different regions of the tumor. Hypoxia, oxidative stress, and inflammation have been identified as positive regulators of metastatic potential, drug resistance, and tumorigenic properties in cancer. It is proven that, Escherichia coli (E. coli) and life-threatening infectious pathogens such as Staphylococcus aureus (SA) and Mycobacterium tuberculosis (Mtb) are noticeably sensitive to alterations in the intracellular oxidative environment.  An alternative emerging paradigm is that many cancers may be promoted by commensal microbiota, either by translocation and adherence of microbes to cancer cells or by the distant release of inflammation-activating microbial metabolites. Microbial factors such as F. nucleatum, B. fragilis, and Enterobacteriaceae members may contribute to disease onset in patients with a hereditary form of colorectal cancer (CRC); familial adenomatous polyposis (FAP). These findings are linked with the creation of new biomarkers and therapy for identifying and treating biofilm-associated cancers.  Currently,  about 20% of neoplasms globally can be caused by infections, with  approximately 1.2 million cases annually. Several antineoplastic drugs that exhibited activity against S. mutans, including tamoxifen, doxorubicin, and ponatinib, also possessed activity against other Gram-positive bacteria. Drug repurposing, also known as repositioning, has gained momentum, mostly due to its advantages over de novo drug discovery, including reduced risk to patients due to previously documented clinical trials, lower drug development costs, and faster benchtop-to-clinic transition. Although many bacteria are carcinogens and tumor promoters, some have shown great potential towards cancer therapy. Several species of bacteria have shown an impressive power to penetrate and colonize solid tumors, which has mainly led to neoplasm slower growth and   tumor clearance.  Different strains of Clostridia, Lactococcus, Bifidobacteria, Shigella, Vibrio, Listeria, Escherichia, and Salmonella have been evaluated against cancer in animal models.  Conclusion. Cancer is a multifactorial disease and the use of bacteria for cancer therapy as an immunostimulatory agent or as a vector for carrying the therapeutic cargo is a promising treatment method. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinliang Gao ◽  
Tao Luo ◽  
Jinke Wang

AbstractAlthough some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPN and LCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.


Oncogenesis ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Na Niu ◽  
Jun Yao ◽  
Robert C. Bast ◽  
Anil K. Sood ◽  
Jinsong Liu

AbstractTo 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.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guangjian Fan ◽  
Lianhui Sun ◽  
Ling Meng ◽  
Chen Hu ◽  
Xing Wang ◽  
...  

AbstractDrug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.


Author(s):  
Shao-An Wang ◽  
Ming-Jer Young ◽  
Yi-Chang Wang ◽  
Shu-Hui Chen ◽  
Chia-Yu Liu ◽  
...  

AbstractDrug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.


Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1787 ◽  
Author(s):  
Hana Sahinbegovic ◽  
Tomas Jelinek ◽  
Matous Hrdinka ◽  
Juli R. Bago ◽  
Marcello Turi ◽  
...  

Cell-to-cell communication is a fundamental process in every multicellular organism. In addition to membrane-bound and released factors, the sharing of cytosolic components represents a new, poorly explored signaling route. An extraordinary example of this communication channel is the direct transport of mitochondria between cells. In this review, we discuss how intercellular mitochondrial transfer can be used by cancer cells to sustain their high metabolic requirements and promote drug resistance and describe relevant molecular players in the context of current and future cancer therapy.


2020 ◽  
Vol 12 (4) ◽  
pp. 325-337
Author(s):  
Brian Kawahara ◽  
Suvajit Sen ◽  
Pradip K Mascharak

Photo-activatable carbon monoxide (CO)-releasing molecules (photoCORMs), have recently provided help to identify the salutary effects of CO in human pathophysiology. Among them notable is the ability of CO to sensitize chemotherapeutic-resistant cancer cells. Findings from our group have shown CO to mitigate drug resistance in certain cancer cells by the inhibition of cystathionine β-synthase (CBS), a key regulator of redox homeostasis in the cell. Diminution of the antioxidant capacity of cancer cells leads to sensitization to reactive oxygen species-producing drugs like doxorubicin and paclitaxel upon cotreatment with CO as well as in mitigating the drug effects of cisplatin. We hypothesize that the development of CO delivery techniques for coadministration with existing cancer treatment regimens may ultimately improve clinical outcomes in cancer therapy.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2157-2157
Author(s):  
Cornelia A Brendel ◽  
Katharina Henkenius ◽  
Melanie Maerken ◽  
Tom Kaiser ◽  
Larissa Greif ◽  
...  

Abstract Inherent or acquired drug resistance is the major obstacle in cancer therapy. An individual prediction of response to cancer therapy would be highly appreciated. It has been reported that the mitochondrial function of cancer cells correlates with the treatment response in different cancer entities (Chonghaile et al., Science 2011 and Vo et al., Cell 2012). However, as the method of BCL-2 peptide priming measurement (“BH3 profiling”) seemed to be rather complicated and error-prone in our hand we sought to determine mitochondrial function by analyzing cellular respiration. We established three different drug resistant human cancer cell lines (MV4-11, HL-60 and NCl-H82) by continuous exposure to Sorafenib, Cytarabine (Ara-C) or Etoposid (VP-16) respectively. Cellular respiration was measured as oxygen consumption rate (OCR) 24h after drug exposure employing the XF96 extracellular Flux Analyzer. Viability, reduction equivalents NADH/NADPH and mitochondrial membrane potential of the cells were concomitantly determined by flow cytometry via 4’, 6-diamidino-2-phenylindole (DAPI) exclusion, (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Tetramethylrhodamine ethyl ester (TMRE) staining with flow cytometric analysis, respectively. All resistant cancer cells maintained their respiration capacity upon exposure to tyrosine kinase inhibitors, chemotherapeutics or topoisomerase inhibitors, whereas the respiration of drug sensitive cancer cells decreased significantly. Moreover, resistant MV4-11 and HL-60 cells exhibited a metabolic shift towards glycolysis after drug treatment. In contrast sensitive cancer cells showed a decline in respiration and glycolysis in a dose dependent manner. Decrease of respiration was evident at 24h post treatment, while the onset of apoptosis was measurable 48-120h later. Reduction equivalents NADH/NADPH but not mitochondrial membrane potential were diminished in sensitive cells after 24h drug exposure, but dose dependency was more distinct with OCR analysis. The increase of glycolysis in resistant cell lines was also not detectable with the MTT assay. Our data indicate cellular metabolism and in particular respiration as an early, sensitive and reliable surrogate parameter of drug sensitivity in viable cells that might therefore be applicable in order to determine drug responsiveness in primary cancer cells in a prospective manner. Disclosures No relevant conflicts of interest to declare.


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