Displaying publications 1 - 20 of 37 in total

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  1. Prabhakaran P, Hassiotou F, Blancafort P, Filgueira L
    Front Oncol, 2013;3:134.
    PMID: 23761858 DOI: 10.3389/fonc.2013.00134
    Breast tumors are heterogeneous including cells with stem cell properties and more differentiated cells. This heterogeneity is reflected into the molecular breast cancer subtypes. Breast cancer stem cells are resistant to chemotherapy, thus recent efforts are focusing on identifying treatments that shift them toward a more differentiated phenotype, making them more susceptible to chemotherapy. We examined whether the drug cisplatin induces differentiation in breast cancer cell lines that represent different breast cancer subtypes. We used three cell lines representing triple-negative breast cancers, BT-549 and MDA-MB-231 (claudin-low), and MDA-MB-468 (basal-like), along with estrogen and progesterone receptor positive MCF-7 cells (luminal). Cisplatin was applied at 2.5, 5, 10, and 20 μM, and cell viability and proliferation were measured using MTS and BrdU assays, respectively. The effect of cisplatin on the cellular hierarchy was examined by flow cytometry, immunofluorescence and qRT-PCR. Cisplatin treatment of 10 and 20 μM reduced cell viability by 36-51% and proliferation capacity by 36-67%. Treatment with cisplatin resulted in 12-67% down-regulation of stem cell markers (CD49f, SSEA4) and 10-130% up-regulation of differentiation markers (CK18, SMA, β-tubulin). At the mRNA level, CD49f was down-regulated whilst β-tubulin was up-regulated in the claudin-low cell lines. SSEA4 protein expression decreased upon cisplatin treatment, but SSEA4 mRNA expression increased indicating a differential regulation of cisplatin at the post-transcriptional level. It is concluded that cisplatin reduces breast cancer cell survival and induces differentiation of stem/progenitor cell subpopulations within breast cancer cell lines. These effects indicate the potential of this drug to target specific chemotherapy-resistant cells within a tumor.
  2. Nin DS, Li F, Visvanathan S, Khan M
    Front Oncol, 2015;5:210.
    PMID: 26500885 DOI: 10.3389/fonc.2015.00210
    Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial for the commitment of primitive hematopoietic cells to cells of myeloid lineage and that misfolded N-CoR may contribute to transformation of committed myeloid cells through the ectopic reactivation of Flt3/CD34-based stem cell phenotypes in promyelocytic and monocytic AML. Moreover, these findings provide novel mechanistic insights into the formation of leukemic stem cells in subsets of AML and identify the misfolded N-CoR as a subtype-specific biomarker of AML.
  3. Wong KK, Hassan R, Yaacob NS
    Front Oncol, 2021;11:624742.
    PMID: 33718188 DOI: 10.3389/fonc.2021.624742
    Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4+ and CD8+ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.
  4. Mustafa MF, Saliluddin SM, Fakurazi S, Tizen Laim NMS, Md Pauzi SH, Nik Yahya NH, et al.
    Front Oncol, 2021;11:612009.
    PMID: 34490076 DOI: 10.3389/fonc.2021.612009
    Mitochondria play important roles in regulating cell bioenergetics status and reactive oxygen species (ROS) generation. ROS-induced mitochondrial damage is among the main intracellular signal inducers of autophagy. Autophagy is a cellular catabolic process that regulates protein and organelle turnover, while a selective form of autophagy, mitophagy, specifically targets dysfunctional mitochondrial degradation. This study aims to measure the levels of autophagy, mitophagy, oxidative stress, and apoptosis in invasive breast carcinoma tissues using immunohistochemistry (IHC). Tissue microarrays of 76 patients with breast cancer were stained with six IHC markers (MnSOD, Beclin-1, LC3, BNIP3, Parkin, and cleaved caspase 3). The expression intensity was determined for each tumor tissue and the adjacent tumor-matched control tissues. Intermediate and strong staining scores of MnSOD, Beclin-1, LC-3, BNIP-3, and Parkin were significantly higher in tumor tissues compared to the adjacent matched control. The scoring intensity was further classified into tissues with negative staining and positive staining, which showed that positive scores of Beclin-1 and Parkin were significantly high in tumor tissues compared to other markers. Positive association was also noted between BNIP-3 and Beclin-1 as well as LC-3 and cleaved caspase-3 immunostaining. To our knowledge, this is one of the first studies that measure both mitophagy and autophagy in the same breast cancer tissues and the adjacent matched control. The findings from this study will be of great potential in identifying new cancer biomarkers and inspire significant interest in applying anti-autophagy therapies as a possible treatment for breast cancer.
  5. Behrooz AB, Syahir A
    Front Oncol, 2021;11:642719.
    PMID: 33869033 DOI: 10.3389/fonc.2021.642719
    Glioblastoma multiforme (GBM) is one of the most lethal forms of primary brain tumors. Glioblastoma stem cells (GSCs) play an undeniable role in tumor development by activating multiple signaling pathways such as Wnt/β-catenin and PI3K/AKT/mTOR that facilitate brain tumor formation. CD133, a transmembrane glycoprotein, has been used to classify cancer stem cells (CSCs) in GBM. The therapeutic value of CD133 is a biomarker of the CSC in multiple cancers. It also leads to growth and recurrence of the tumor. More recent findings have confirmed the association of telomerase/TERT with Wnt/β-catenin and the PI3K/AKT/mTOR signaling pathways. Advance studies have shown that crosstalk between CD133, Wnt/β-catenin, and telomerase/TERT can facilitate GBM stemness and lead to therapeutic resistance. Mechanistic insight into signaling mechanisms downstream of surface biomarkers has been revolutionized by facilitating targeting of tumor-specific molecular deregulation. This review also addresses the importance of interplay between CD133, Wnt/β-catenin and TERT signaling pathways in GSCs and outlines the future therapeutic goals for glioblastoma treatment.
  6. Zakaria N, Mohd Yusoff N, Zakaria Z, Widera D, Yahaya BH
    Front Oncol, 2018;8:166.
    PMID: 29868483 DOI: 10.3389/fonc.2018.00166
    Cancer stem cells (CSCs) are a subpopulation of cancer cells that play a pivotal role in tumor development, invasion, metastasis, and recurrence. We and others have reported significant involvement of the NF-κB pathway in regulating CSCs of non-small cell lung cancer (NSCLC). In this study, we evaluated the effects of NF-κB inhibition on self-renewal, stemness, migration, and expression of genes involved in the epithelial to mesenchymal transition (EMT) and apoptosis resistance in lung CSCs. Different concentrations of the NF-κB inhibitor BMS-345541 (0.4, 4.0, and 10.0 µM), an inhibitor the NF-κB upstream kinase IKKβ, were used to treat both lung CSCs (CD166+CD44+, CD166+EpCAM+) and non-CSC NSCLC cells (CD166-CD44-, CD166-EpCAM-) in A549 and H2170 cell lines. We assessed the impact of BMS-345541 on the ability to form tumorspheres (self-renewal assay), expression of stemness genes (SOX2, OCT4, NANOG, SCA-1, and KLF4), migration, and expression of EMT and apoptosis-related genes. Inhibition of NF-κB by BMS-345541 effectively reduced the stemness, self-renewal, and migration capacity of lung CSCs. Moreover, expression of genes involved in the EMT (SNAI1 and TWIST) and apoptosis resistance (BCL-2, BAX, and BIRC5) was significantly reduced following the treatments, suggesting that NF-κB inhibition is sufficient to prevent the EMT and induce apoptosis in lung CSCs. Our findings suggest that NF-κB inhibition could reduce the capability of CSCs to maintain their population within the tumor mass, potentially decelerating cancer progression, relapse, and chemotherapy resistance.
  7. Zakaria N, Satar NA, Abu Halim NH, Ngalim SH, Yusoff NM, Lin J, et al.
    Front Oncol, 2017;7:80.
    PMID: 28529925 DOI: 10.3389/fonc.2017.00080
    Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. Non-small cell lung cancer (NSCLC), which is one of two types of lung cancer, accounts for 85-90% of all lung cancers. Despite advances in therapy, lung cancer still remains a leading cause of death. Cancer relapse and dissemination after treatment indicates the existence of a niche of cancer cells that are not fully eradicated by current therapies. These chemoresistant populations of cancer cells are called cancer stem cells (CSCs) because they possess the self-renewal and differentiation capabilities similar to those of normal stem cells. Targeting the niche of CSCs in combination with chemotherapy might provide a promising strategy to eradicate these cells. Thus, understanding the characteristics of CSCs has become a focus of studies of NSCLC therapies.
  8. Prayuenyong P, Taylor JA, Pearson SE, Gomez R, Patel PM, Hall DA, et al.
    Front Oncol, 2018;8:363.
    PMID: 30319960 DOI: 10.3389/fonc.2018.00363
    Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer. Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized. Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin. Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed.
  9. Ab Razak NS, Ab Mutalib NS, Mohtar MA, Abu N
    Front Oncol, 2019;9:1113.
    PMID: 31803605 DOI: 10.3389/fonc.2019.01113
    Chemotherapy is the standard go-to treatment for cancer besides surgery and radiation. It has recently come to light that the interaction between chemotherapy and the immune system is important in maintaining tumor immunity as well as influencing the efficacy of the therapy. However, ample preclinical studies have shown that in addition to direct cytotoxic effects on cancer cells, a fraction of chemotherapeutic agents may promote immunogenic cell death, and alter the inflammatory milieu of the tumor microenvironment. Extracellular vesicles (EV) have been shown to interact with the tumor microenvironment by delivering alterative signals to the surrounding cells; as a result, this results in interference with each cell's capability to eradicate tumors or gives advantages to cancer cells so as to survive therapy. Chemotherapy-induced extracellular vesicles (chemo-EVs) have been theorized to be carrying different cargo loads than non-chemotherapy-induced EVs. Aside from chemoresistance, there is growing evidence to suggest that chemo-EVs could dictate tumor behavior, especially in terms of metastasis, immune response, and cancer stemness. This mini-review attempts to summarize and evaluate recent developments on the role of chemo-EVs in other aspects of tumor-related processes.
  10. Jayasingam SD, Citartan M, Thang TH, Mat Zin AA, Ang KC, Ch'ng ES
    Front Oncol, 2019;9:1512.
    PMID: 32039007 DOI: 10.3389/fonc.2019.01512
    Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.
  11. Tan SY, Visvanathan S, Abu Hassan R, Khan M
    Front Oncol, 2019;9:1335.
    PMID: 31850220 DOI: 10.3389/fonc.2019.01335
    Hepatitis B virus (HBV) is causally linked to hepatocellular injury and cell death, which are followed by hepatocellular carcinoma (HCC) after a long latent period. The HBV derived X protein (HBX) is the most potent carcinogenic factor for HCC, however, the molecular mechanism of HBX-induced transformation of hepatic cells in HCC is poorly understood. We have shown that nuclear receptor co-repressor (NCoR) is essential for the spatial repression of global transcription by the promyelocytic leukemia oncogenic domains (PODs), a frequent target of viral oncoproteins like HBX and that disintegration of PODs due to misfolded conformation dependent loss (MCDL) of NCoR is linked to promyelocytic and monocytic acute myeloid leukemia (AML). Given the key role of NCoR in cellular homeostasis across various tissue subtypes, we hypothesized that HBX-induced MCDL of NCoR might be linked to HCC through similar mechanism. Based on this hypothesis, the conformation of NCoR in HCC derived tumor cells and primary human tissue sections were analyzed and a selective MCDL of NCoR in HBX positive HCC cells was identified. HBX triggered the misfolding of NCoR through ubiquitination, followed by its degradation by autophagy, thus suggesting a cross talk between ubiquitin proteasome system (UPS) and autophagy lysosomal pathway (ALP) in MCDL of NCoR in HBX positive HCC cells. SiRNA-induced NCoR ablation selectively impaired the growth and survival of HBX positive HCC cells, suggesting a role of MCDL in the growth and survival of HBX positive HCC cells. These finding identify a possible crosstalk between UPS and ALP in the misfolding and loss of NCoR in HBX positive HCC cells and suggest a role of autophagic recycling of misfolded NCoR in the activation of oncogenic metabolic signaling in HCC. The misfolded NCoR reported in this study represents a novel conformation based molecular target which could be valuable in the design and development of tumor cell specific diagnostic and therapeutic approach for HBX positive HCC.
  12. Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY
    Front Oncol, 2019;9:48.
    PMID: 30847297 DOI: 10.3389/fonc.2019.00048
    Signal Transducer and Activator of Transcription (STAT) pathway is connected upstream with Janus kinases (JAK) family protein and capable of integrating inputs from different signaling pathways. Each family member plays unique functions in signal transduction and crucial in mediating cellular responses to different kind of cytokines. STAT family members notably STAT3 and STAT5 have been involved in cancer progression whereas STAT1 plays opposite role by suppressing tumor growth. Persistent STAT3/5 activation is known to promote chronic inflammation, which increases susceptibility of healthy cells to carcinogenesis. Here, we review the role of STATs in cancers and inflammation while discussing current therapeutic implications in different cancers and test models, especially the delivery of STAT3/5 targeting siRNA using nanoparticulate delivery system.
  13. Kampan NC, Teik CK, Shafiee MN
    Front Oncol, 2022;12:999749.
    PMID: 36408149 DOI: 10.3389/fonc.2022.999749
    Lymph node involvement is a major predictive indicator in early-stage epithelial ovarian cancer (EOC). There is presently no effective way to determine lymph node involvement other than surgical staging. As a result, traditional ovarian cancer surgery still includes pelvic and paraaortic lymphadenectomy. However, it might be linked to higher blood loss, lengthier operations, and longer hospital stays. The creation of a technique for accurately predicting nodal status without significant lymphadenectomy is thus the subject of ongoing research. Sentinel lymph nodes (SLN) mapping is a routine procedure in oncological surgery and has been proven to be effective and safe in cervical, vulvar, and uterine cancer. On the other hand, SLN mapping is not yet widely accepted and recognized in EOC. A thorough search of the literature was conducted between January 1995 to March 2022, using PubMed and Embase. This review included studies on lymphatic outflow of the ovaries and the sentinel lymph node method. A total of 13 studies involving 212 patients who underwent sentinel lymph node mapping for ovaries were included. Both open and laparoscopic approach are used. The most popular injection site is the ovarian ligaments, and a variety of agents are utilized, although the main markers were, technetium-99m radiocolloid (Tc-99m) or indocyanine green, either alone or in combination. Overall detection rate for SLN in ovaries is 84.5% (interquartile range: 27-100%). We suggest a standardized method for sentinel lymph node mapping in ovarian cancer. The detection rates, characterization and true positive rates of the approach in investigations support further study. The use of ultra-staging is essential for lower-volume metastasis and reproducibility. To ascertain the clinical utility of sentinel node in early ovarian cancer, larger collaborative prospective clinical trials are necessary.
  14. Jia H, Zhao B, Zhang F, Santhanam RK, Wang X, Lu J
    Front Oncol, 2021;11:785455.
    PMID: 34912721 DOI: 10.3389/fonc.2021.785455
    Polysaccharides are the main active ingredients of ginseng. To extract the most effective polysaccharides against hepatocellular carcinoma (HCC), we isolated and characterized the polysaccharides from the mountain cultivated ginseng (MCG) and compared their composition and cytotoxic effect with cultivated ginseng (CG) polysaccharide against HepG2 cell lines for the first time. MCG polysaccharides and CG polysaccharides were fractionated into two fractions such as MTPS-1, MTPS-2 and CTPS-1, CTPS-2 by salting out, respectively. Compared to CG, MCG possessed appreciable cytotoxic effect against HepG2 cells among that MTPS-1 possess fortified effect. Then, MTPS-1 was selected for further isolation process and seven acidic polysaccharides (MCGP-1-MCGP-7) were obtained using ethanol precipitation, ion-exchange, and gel permeation chromatography techniques. Structural characteristics of the polysaccharides (MCGP-1-MCGP-7) were done by adapting methylation/GC-MS and NMR analysis. Overall, MCGP-3 polysaccharide was found to possess significant cytotoxic effect against HepG2 cells with the IC50 value.
  15. Tang ZN, Hu LH, Soh HY, Yu Y, Zhang WB, Peng X
    Front Oncol, 2021;11:715484.
    PMID: 35096559 DOI: 10.3389/fonc.2021.715484
    Objective: To evaluate the feasibility and accuracy of mixed reality combined with surgical navigation in oral and maxillofacial tumor surgery.

    Methods: Retrospective analysis of data of seven patients with oral and maxillofacial tumors who underwent surgery between January 2019 and January 2021 using a combination of mixed reality and surgical navigation. Virtual surgical planning and navigation plan were based on preoperative CT datasets. Through IGT-Link port, mixed reality workstation was synchronized with surgical navigation, and surgical planning data were transferred to the mixed reality workstation. Osteotomy lines were marked with the aid of both surgical navigation and mixed reality images visualized through HoloLens. Frozen section examination was used to ensure negative surgical margins. Postoperative CT datasets were obtained 1 week after the surgery, and chromatographic analysis of virtual osteotomies and actual osteotomies was carried out. Patients received standard oncological postoperative follow-up.

    Results: Of the seven patients, four had maxillary tumors and three had mandibular tumors. There were total of 13 osteotomy planes. Mean deviation between the planned osteotomy plane and the actual osteotomy plane was 1.68 ± 0.92 mm; the maximum deviation was 3.46 mm. Chromatographic analysis showed error of ≤3 mm for 80.16% of the points. Mean deviations of maxillary and mandibular osteotomy lines were approximate (1.60 ± 0.93 mm vs. 1.86 ± 0.93 mm). While five patients had benign tumors, two had malignant tumors. Mean deviations of osteotomy lines was comparable between patients with benign and malignant tumors (1.48 ± 0.74 mm vs. 2.18 ± 0.77 mm). Intraoperative frozen pathology confirmed negative resection margins in all cases. No tumor recurrence or complications occurred during mean follow-up of 15.7 months (range, 6-26 months).

    Conclusion: The combination of mixed reality technology and surgical navigation appears to be feasible, safe, and effective for tumor resection in the oral and maxillofacial region.

  16. Palaniandy K, Kamarudin Z, Wong YP, Mohamed Mukari SA, Jiau WXH, Bakar AA
    Front Oncol, 2022;12:1012395.
    PMID: 36452494 DOI: 10.3389/fonc.2022.1012395
    Secondary malignancies following radiotherapy are well documented, with an estimated incidence of 5%. These may manifest as carcinomas, gliomas, or sarcomas within the previous radiation field. Glioblastoma multiforme following radiotherapy for nasopharyngeal carcinoma is an uncommon occurrence and carries a poor prognosis, whereas papillary thyroid carcinoma following radiotherapy is well documented, though the exact incidence is not well documented. The occurrence of synchronous radiotherapy-induced malignancy over both sites has not been described in the literature before. We describe a middle-aged gentleman diagnosed with glioblastoma multiforme and papillary thyroid carcinoma 6 years after radiotherapy for nasopharyngeal carcinoma. Though our case is the first reported case of a synchronous tumour of its nature, it is likely that such cases are under-reported. Long-term vigilance for loco-regional radiotherapy-induced secondary malignancies is a must, and the presence of a second distinct secondary malignancy must be entertained.
  17. Kalamegam G, Sait KHW, Ahmed F, Kadam R, Pushparaj PN, Anfinan N, et al.
    Front Oncol, 2023;13:1171430.
    PMID: 37020874 DOI: 10.3389/fonc.2023.1171430
    [This corrects the article DOI: 10.3389/fonc.2018.00592.].
  18. Zulaziz N, Chai SJ, Lim KP
    Front Oncol, 2023;13:1151373.
    PMID: 37035187 DOI: 10.3389/fonc.2023.1151373
    Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is often preceded by chronic inflammation such as liver fibrosis and cirrhosis. Different cell types are believed to give rise to liver-specific cancer associated fibroblast (CAF), these include resident fibroblast, hepatic stellate cell, liver cancer cell, hepatic sinusoidal endothelial cell and mesenchymal stromal cell. The abundance of fibroblasts has contributed to the cancer progression, immune modulation and treatment resistance in HCC. In this review, we discussed the origins, subtypes and roles of cancer associated fibroblasts in HCC. Their specific roles in shaping the tumor microenvironment, facilitating cancer growth, and modulating different immune cell types to confer a permissive environment for cancer growth. CAF is now an attractive therapeutic target for cancer treatment, however specific therapeutic development in HCC is still lacking. Hence, we have included preclinical and clinical development of CAF-specific interventions for other cancer types in this review. However, most CAF-specific therapies have resulted in disappointing clinical outcomes, likely due to the difficulties in differentiating CAF from normal fibroblast. A thorough understanding of the characteristics and functionalities of CAF is warranted to further improve the therapeutic efficacy of anti-CAF therapies.
  19. Kalamegam G, Sait KHW, Ahmed F, Kadam R, Pushparaj PN, Anfinan N, et al.
    Front Oncol, 2018;8:592.
    PMID: 30581772 DOI: 10.3389/fonc.2018.00592
    Ovarian cancer is a highly lethal and the second highest in mortality among gynecological cancers. Stem cells either naïve or engineered are reported to inhibit various human cancers in both in-vitro and in-vivo. Herein we report the cancer inhibitory properties of human Wharton's jelly stem cell (hWJSC) extracts, namely its conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against two ovarian cancer cell lines (OVCAR3 and SKOV3) in-vitro. Cell metabolic activity assay of OVCAR3 and SKOV3 cells treated with hWJSC-CM (12.5, 25, 50, 75, 100%) and hWJSC-CL (5, 10, 15, 30, and 50 μg/ml) demonstrated concentration dependent inhibition at 24-72 h. Morphological analysis of OVCAR3 and SKOV3 cells treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (15, 30, and 50 μg/ml) for 24-72 h showed cell shrinkage, membrane damage/blebbings and cell death. Cell cycle assay demonstrated an increase in the sub-G1 and G2M phases of cell cycle following treatment with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, and 30 μg/ml) at 48 h. Both OVCAR3 and SKOV3 cells demonstrated mild positive expression of activated caspase 3 following treatment with hWJSC-CM (50%) and hWJSC-CL (15 μg/ml) for 24 h. Cell migration of OVCAR3 and SKOV3 cells were inhibited following treatment with hWJSC-CM (50%) and hWJSC-CL (15 μg/ml) for 48 h. Tumor spheres (TS) of OVCAR3 and SKOV3 treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, 30 μg/ml) for 48 h showed altered surface changes including vacuolations and reduction in size of TS. TS of OVCAR3 and SKOV3 also showed the presence of few ovarian cancer stem cells (CSCs) in minimal numbers following treatment with hWJSC-CM (50%) or hWJSC-CL (15 μg/ml) for 48 h. Real-time gene expression analysis of OVCAR3 and SKOV3 treated with hWJSC-CM (50%) or hWJSC-CL (15 μg/ml) for 48 h demonstrated decreased expression of cell cycle regulatory genes (cyclin A2, Cyclin E1), prostaglandin receptor signaling genes (EP2, EP4) and the pro-inflmmatory genes (IL-6, TNF-α) compared to untreated controls. The results indicate that hWJSC-CM and hWJSC-CL inhibit ovarian cancer cells at mild to moderate levels by inducing cellular changes, cell cycle arrest, apoptosis, decreasing the expression of CSC markers and related genes regulation. Therefore, the stem cell factors in hWJSCs extracts can be useful in cancer management.
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