Showing papers in "Medical Oncology in 2021"
TL;DR: In this article, the tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells.
Abstract: Metastasis is the most complex and deadly event. Tumor-stromal interface is a place where invasion of tumor cells in the form of single-cell or collective migration occurs, with the latter being less common but more efficient. Initiation of metastasis relies on the tumor cell cross-talking with stromal cells and taking an epithelial-mesenchymal transition (EMT) in single cells, and a hybrid EMT in collective migratory cells. Stromal cross-talking along with an abnormal leaky vasculature facilitate intravasation of tumor cells, here the cells are called circulating tumor cells (CTCs). Tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells. CTCs will adhere to the interstituim of the secondary organ/s, within which the newly arrived disseminative tumor cells (DTCs) undergo either dormancy or proliferation. Metastatic outgrowth is under the influence of several factors, such as the activity of macrophages, impaired autophagy and secondary site inflammatory events. Metastasis can be targeted by multiple ways, such as repressing the promoters of pre-metastatic niche (PMN) formation, suppressing environmental contributors, such as hypoxia, oxidative and metabolic stressors, and targeting signaling and cell types that take major contribution to the whole process. These strategies can be used in adjuvant with other therapeutics, such as immunotherapy.
102 citations
TL;DR: The exosomes' roles in different mechanisms underlying cancer progression for the rational design of tailored strategies against this illness are summarized and the new findings on using these smart vesicles as therapeutic targets and potential biomarkers are highlighted.
Abstract: Exosomes are extracellular nanovesicles secreted from almost all types of normal and cancer cells. Collective evidence suggests that exosomes participate in cell-cell communication via transmitting their cargo, including nucleic acids, proteins, and metabolites to recipient cells. Tumor-derived exosomes (TEXs) play prominent roles in the regulation of molecular pathways in malignancies. Internalization of exosomes by tumor cells affects cellular pathways and several cancer hallmarks, including reprogramming of stromal cells, modulating immune responses, reconstructing extracellular matrix architecture, or even endowing tumor cells with drug features resistance. The unique biogenesis pathways of exosomes, their composition, low immunogenicity, and nontoxicity, together with their ability to target tumor cells, bring them up as an attractive vesicles for cancer therapy. Thus, understanding the molecular mechanisms of exosomes' participation in tumorigenesis will be critical for the next generation of cancer therapeutics. This review aims to summarize the exosomes' roles in different mechanisms underlying cancer progression for the rational design of tailored strategies against this illness. The present study also highlights the new findings on using these smart vesicles as therapeutic targets and potential biomarkers. Recent advances in exosome biology will open up new, more effective, less invasive, and more individualized clinical applications for treating cancer patients.
34 citations
TL;DR: In this article, the authors summarized the available scientific literature regarding the molecular links between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and cancer, which make the cancer patients highly susceptible to COVID-19.
Abstract: The COVID-19 pandemic has engulfed the entire world and has claimed more than 3 million lives worldwide. This viral disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mainly characterized by fever, dry cough, fatigue, anosmia, anorexia, and dyspnea. The severity of the disease increases with age and presence of comorbidities, including cancer. Multiple clinical studies have shown that the cancer patients are highly susceptible to the severe form of the viral disease. In this review article, we have summarized the available scientific literature regarding the molecular links between COVID-19 and cancer, which make the cancer patients highly susceptible to COVID-19. Few studies have shown that the angiotensin-converting enzyme 2 (ACE2) receptor, transmembrane protease serine 2 (TMPRSS2), and the immune response and inflammation establish the interconnection between the two diseases. Additionally, we have also discussed whether SARS-CoV-2 can contribute to cancer development in COVID-19 patients. A recent study has suggested that SARS-CoV-2 may create a microenvironment that may support cancer cell proliferation and induce the activation of dormant cancer cells (DCCs). In another study, the blood sera of COVID-19 patients were found to activate epithelial-to-mesenchymal transition (EMT) in cancer cells. Overall, this review article will surely help the scientific community to understand why the cancer patients are so much prone to COVID-19 and will also motivate the researchers to find new therapeutic strategies that may save the lives of many COVID-19-infected cancer patients.
27 citations
TL;DR: In this article, a review article deals with reviewing the scientific literature on the PI3K/Akt/mTOR pathway inhibitors listed in the National Cancer Institute (NCI) drug dictionary and proved effective against multiple cancers.
Abstract: Chronic myeloid leukemia (CML), a myeloproliferative hematopoietic cancer, is caused by a genetic translocation between chromosomes 9 and 22. This translocation produces a small Philadelphia chromosome, which contains the Bcr-Abl oncogene. The Bcr-Abl oncogene encodes the BCR-ABL protein, upregulates various signaling pathways (JAK-STAT, MAPK/ERK, and PI3K/Akt/mTOR), and out of which the specifically highly active pathway is the PI3K/Akt/mTOR pathway. Among early treatments for CML, tyrosine kinase inhibitors (TKIs) were found to be the most effective, but drug resistance against kinase inhibitors led to the discovery of novel alternative therapies. At this point, the PI3K/Akt/mTOR pathway components became new targets due to stimulation of this pathway in TKIs-resistant CML patients. The current review article deals with reviewing the scientific literature on the PI3K/Akt/mTOR pathway inhibitors listed in the National Cancer Institute (NCI) drug dictionary and proved effective against multiple cancers. And out of those enlisted inhibitors, the US FDA has also approved some PI3K inhibitors (Idelalisib, Copanlisib, and Duvelisib) and mTOR inhibitors (Everolimus, Sirolimus, and Temsirolimus) for cancer therapy. So far, several inhibitors have been tested, and further investigations are still ongoing. Even in Imatinib, Nilotinib, and Ponatinib-resistant CML cells, a dual PI3K/mTOR inhibitor, BEZ235, showed antiproliferative activity. Therefore, by considering the literature data of these reviews and further examining some of the reported inhibitors, which proved effective against the PI3K/Akt/mTOR signaling pathway in multiple cancers, may improve the therapeutic approaches towards TKI-resistant CML cells where the respective signaling pathway gets upregulated.
24 citations
TL;DR: Results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib, suggesting that this combination therapy is a powerful potential application against HCC.
Abstract: The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.
18 citations
TL;DR: The role of gene recurrence scores like oncotype Dx and mammaprint is evolving and can be used as an aid for adjuvant chemotherapy for early stage breast cancer is uncertain and not commonly used as mentioned in this paper.
Abstract: Unlike female breast cancer, male breast cancer (MBC) is rare and not very well understood. Prospective data in the management of MBC are lacking and majority of treatment strategies are adopted from the established guidelines for breast cancer in women. The understanding of biology, clinical presentation, genetics, and management of MBC is evolving but there still remains a large knowledge gap due to the rarity of this disease. Older age, high estradiol levels, klinefelter syndrome, radiation exposure, gynecomastia, family history of breast cancer, BRCA2 and BRCA1 mutation are some of the known risk factors for MBC. Routine screening mammography is not recommended for asymptomatic men. Diagnostic mammogram with or without ultrasound should be considered if there is a suspicion for breast mass. Majority of men with early-stage breast cancer undergo mastectomy whereas breast conserving surgery (BCS) with sentinel lymph node biopsy (SLNB) remains an alternative option in selected cases. Since the majority of MBC are hormone receptor positive (HR+), adjuvant hormonal therapy is required. Tamoxifen for a total of 5 to 10 years is the mainstay adjuvant hormonal therapy. The role of neoadjuvant and adjuvant chemotherapy for early-stage breast cancer is uncertain and not commonly used. The role of gene recurrence scores like oncotype Dx and mammaprint is evolving and can be used as an aid for adjuvant chemotherapy. Majority of metastatic MBC are treated with hormonal therapy with either tamoxifen, gonadotropin-releasing hormone agonist (GnRH) with aromatase inhibitors (AI), or fulvestrant. Chemotherapy is reserved for patients with visceral crisis or rapidly growing tumors.
18 citations
TL;DR: In this paper, the authors investigated the cytotoxic and anti-proliferative effects of bexarotene in C6 glioma cells through the PPARγ/NF-κB pathway.
Abstract: Gliomas are one of the most aggressive brain tumors with a poor prognosis in the central nervous system. Bexarotene is a third-generation retinoid X receptor agonist that is promising in the treatment of both cancer and neurodegenerative diseases. In this study, we aimed to investigate the cytotoxic and anti-proliferative effects of bexarotene in C6 glioma cells through the PPARγ/NF-κB pathway. In the study, first cytotoxic bexarotene concentrations for C6 cells were detected, and then apoptosis profile, reactive oxygen species (ROS), total antioxidant (TAS), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nuclear factor-κB (NF-κB) levels in the cells were determined. In addition, peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression analysis was carried out. As a result, we detected concentration- and time-dependent antiproliferative effects of bexarotene on C6 cells. We found that bexarotene treatment decreased NF-κB and TAS levels and increased PPARγ and 8-OHdG levels in C6 cells. Bexarotene enhanced PPARγ expression in a dose-dependent manner when compared to the control group (P < 0.01). Furthermore, we determined that bexarotene-induced apoptotic C6 cells enhanced through Annexin V-FITC/PI staining and caspase-3/-7 activation analyses since phosphatidylserine level on the outer surface of the cell membrane and caspase-3/-7 activities were increased in the cells treated with bexarotene. In conclusion, bexarotene treatment in C6 glioma cells could modulate apoptosis profile, DNA damage, ROS production, and reduction of TAS levels through inhibition of NF-κB by enhancing PPARγ expression.
15 citations
TL;DR: In this paper, the anti-cancer and anti-metastatic potential of luteolin targeting various transcription factors, markers and signaling pathways associated with the repression of epithelial to mesenchymal transition is discussed.
Abstract: Epithelial to mesenchymal transition (EMT) is a physiological process that assumes a primary role in the induction of cancer metastasis. This results in increased cell renewal, and resistance to cell death and therapies. EMT, therefore, represents an effective strategy for regulating cancerous cell activity. A need for efficacy and low cytotoxicity epithelial to mesenchymal transition modifying drugs has led to the investigational testing of the efficacy of plethora of different groups of phytonutrients. Luteolin is a natural flavonoid inhibits the growth of cancer cells by various mechanisms, such as the stimulation of cancer cell apoptosis, cell cycle arrest, inhibition of cell replication, tumor growth, improvement of drug resistance, prevention of cancer cell intrusiveness and metastasis. This review article focuses on the anti-cancer and anti-metastatic potential of luteolin targeting various transcription factors, markers and signaling pathways associated with the repression of epithelial to mesenchymal transition.
14 citations
TL;DR: In this article, a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features were identified. But, they were presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality.
Abstract: Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naive PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains-in particular, Ki67 and CyclinD1-when presented with such cases in their day to day clinical practice.
14 citations
TL;DR: This pilot study shows that adoption of a PL intervention during curative radiotherapy of breast cancer patients is feasible and able to reduce fat mass and daily outdoor activity could eliminate vitamin D deficiency (vitamin D < 20 ng/ml).
Abstract: Evolutionary principles are rarely considered in clinical oncology. We here aimed to test the feasibility and effects of a dietary and physical activity intervention based on evolutionary considerations in an oncological setting. A total of 13 breast cancer patients referred to our clinic for curative radiotherapy were recruited for this pilot study. The women were supposed to undertake a “Paleolithic lifestyle” (PL) intervention consisting of a Paleolithic diet and daily outdoor activity of at least 30 min duration while undergoing radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters were assessed before, during, and at the end of radiotherapy. A control group on an unspecified standard diet (SD) was assigned by propensity score matching. A total of eleven patients completed the study. The majority of patients (64%) reported feeling good or very good during the intervention. The intervention group experienced an average decrease of 0.4 kg body weight (p < 0.001) and 0.34 kg (p < 0.001) fat mass per week, but fat-free and skeletal muscle mass were not significantly affected. Vitamin D levels increased slightly from 23.8 (11–37.3) ng/ml to 25.1 (22.6–41.6) ng/ml (p = 0.053). β-hydroxybutyrate levels were significantly increased and triglycerides and free T3 hormone levels significantly reduced by the PL intervention. This pilot study shows that adoption of a PL intervention during curative radiotherapy of breast cancer patients is feasible and able to reduce fat mass. Daily outdoor activity could eliminate vitamin D deficiency (vitamin D < 20 ng/ml). Future studies are needed to confirm these findings.
14 citations
TL;DR: In this paper, the characteristic surface markers of cancer stem cells (CSCs) in colorectal cancer and the related mechanism of drug resistance were discussed in detail, and a better understanding of the mechanism of CSCs resistance to chemotherapy may lead to better targeted therapy.
Abstract: The incidence and mortality of colorectal cancer (CRC) have always been among the highest in the world, although the diagnosis and treatment are becoming more and more advanced. At present, the main reason is that patients have acquired drug resistance after long-term conventional drug treatment. An increasing number of evidences confirm the existence of cancer stem cells (CSCs), which are a group of special cells in cancer, only a small part of cancer cells. These special cell populations are not eliminated by chemotherapeutic drugs and result in tumor recurrence and metastasis after drug treatment. CSCs have the ability of self-renewal and multidirectional differentiation, which is associated with the occurrence and development of cancer. CSCs can be screened and identified by related surface markers. In this paper, the characteristic surface markers of CSCs in CRC and the related mechanism of drug resistance will be discussed in detail. A better understanding of the mechanism of CSCs resistance to chemotherapy may lead to better targeted therapy.
TL;DR: In this paper, the gene expression profiles of patients with colorectal cancer were analyzed with the aim of better understanding the molecular mechanism and key genes in CRC, and the most important dysregulated pathways were regulation of cell proliferation, biocarbonate transport, Wnt and IL-17 signaling pathways, and nitrogen metabolism.
Abstract: Colorectal cancer (CRC) is one of the most common malignant tumor and prevalent cause of cancer-related death worldwide. In this study, we analyzed the gene expression profiles of patients with CRC with the aim of better understanding the molecular mechanism and key genes in CRC. Four gene expression profiles including, GSE9348, GSE41328, GSE41657, and GSE113513 were downloaded from GEO database. The data were processed using R programming language, in which 319 common differentially expressed genes including 94 up-regulated and 225 down-regulated were identified. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were conducted to find the most significant enriched pathways in CRC. Based on the GO and KEGG pathway analysis, the most important dysregulated pathways were regulation of cell proliferation, biocarbonate transport, Wnt, and IL-17 signaling pathways, and nitrogen metabolism. The protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software and hub genes including MYC, CXCL1, CD44, MMP1, and CXCL12 were identified as the most critical hub genes. The present study enhances our understanding of the molecular mechanisms of the CRC, which might potentially be applied in the treatment strategies of CRC as molecular targets and diagnostic biomarkers.
TL;DR: In this article, the authors highlighted the added vulnerability of cancer patients to the COVID-19 infection and explored the immunological challenges associated with malignancy, anticancer treatment and vaccination.
Abstract: With the emergence of second wave of COVID-19 infection globally, particularly in India in March-April 2021, protection by massive vaccination drive has become the need of the hour. Vaccines have been proved to reduce the risk of developing severe illness and are emerging as vital tools in the battle against COVID-19. As per the GLOBOCAN database, nearly 19.3 million new cancer cases have been reported in 2020 globally, which posed a significant challenge to health care providers to protect such large number of 'vulnerable' patients from COVID-19. Nevertheless, a considerable degree of doubt, hesitancy and misconceptions are noted regarding the administration of vaccines particularly during active immuno-suppressant treatment. This review article highlights the added vulnerability of cancer patients to the COVID-19 infection and has explored the immunological challenges associated with malignancy, anticancer treatment and COVID-19 vaccination.
TL;DR: In this article, the role of Bortezomib in the cytotoxic effects of Docetaxel on MCF7 cells response and its correlation with Apaf-1 expression level was examined.
Abstract: Chemoresistance is the leading cause of limiting long-term treatment success in cancer cells. Anticancer drugs usually kill cells through apoptosis induction and defects in this signaling pathway lead to chemoresistance. Apoptotic protease activating factor 1 regulates cellular stress evoked by chemotherapeutic agents through facilitating apoptosome assembling but can be degraded by proteasome. This study examined the role of proteasome inhibitor Bortezomib in the cytotoxic effects of Docetaxel on MCF7 cells response and its correlation with Apaf-1 expression level. MTT assay, caspase 3/7 activity assay, propidium iodide staining, adenosine triphosphate and reactive oxygen species amount measurements were utilized to demonstrate the role of Bortezomib in Docetaxel efficacy with and without Apaf-1 overexpressing. Meanwhile, two-dimensional cell migration assay was performed by scratch wound assay. The combination of Docetaxel with Bortezomib was significantly more cytotoxic compared single drug, more effectively delayed cell growth, reduced ATP level and increased ROS production. In Apaf-1 overexpressing, Docetaxel was more efficient in preventing cell migration, however, Docetaxel plus Bortezomib were not significantly effective; and fluorescence images supported the interpretation. Our findings demonstrated MCF7 resistance to Docetaxel is due in part to low Apaf-1 level and Apaf-1 overexpression resulted in the increase of cell susceptibility to Docetaxel stimulus. We assume that proteasome inhibitor may restore apoptotic proteins like Apaf-1 and prevent the degradation of cytosolic cytochrome c released by Docetaxel, consequently triggering intrinsic apoptosis and promoting cancer cell death. Collectively, treating MCF7 breast cells with proteasome inhibitor sensitizes cells to Docetaxel-induced apoptosis and possibly overcomes chemoresistance.
TL;DR: In this paper, the authors attempted to identify the key genes and pathways in the obesity-induced development of hepatocellular carcinoma (HCC) using integrated bioinformatics analyses, and the results demonstrated that these dysregulated genes in both obesity and HCC may serve as considerable targets for the prevention and treatment of HCC development in obese individuals.
Abstract: Obesity, which has become one of the biggest public health problems of the twenty-first century, accompanies many chronic conditions, including cancer. On the other hand, liver cancer, which is known to be associated with obesity, is considered another serious threat to public health. However, the underlying drivers of the development of obesity-associated hepatocellular carcinoma (HCC) remain blurry. The current study attempted to identify the key genes and pathways in the obesity-induced development of HCC using integrated bioinformatics analyses. Obesity and HCC-associated gene expression datasets were downloaded from Gene Expression Omnibus (GEO) and analyzed to identify overlapping differentially expressed genes (DEGs) and hub genes. The prognostic potentials, survival analysis, and expression levels of hub genes were further assessed. Moreover, the correlation between hub genes and the immune cells infiltration was analyzed. The findings of this research revealed that both mRNA and protein expression levels of the four hub genes (IGF1, ACADL, CYP2C9, and G6PD) involved in many important metabolic pathways are remarkably altered in both obese individuals and patients with HCC. The results demonstrated that these dysregulated genes in both obesity and HCC may serve as considerable targets for the prevention and treatment of HCC development in obese individuals.
TL;DR: In this article, the authors summarize the current knowledge regarding prostate specific membrane antigen (PSMA) diagnostics and PSMA ligand therapies and discuss their implication in the treatment of advanced prostate cancer.
Abstract: Although management of advanced prostate cancer is evolving, a lot of work remains to be done for patients who have exhausted all options. Molecular targeting of prostate specific membrane antigen (PSMA) is valuable not only for diagnostic but also for therapeutic reasons. PSMA is thus considered to be useful in a theranostic approach. PSMA scans are upcoming diagnostic modalities which detect metastatic lesions that are missed by conventional imaging modalities. PSMA ligand therapy is also an upcoming treatment modality that has been proven to be beneficial with minimal toxicity in patients with advanced prostate cancer that have progressed on prior therapy. In this review article, we summarize the current knowledge regarding PSMA diagnostics and PSMA ligand therapies and discuss their implication in the treatment of advanced prostate cancer.
TL;DR: In this paper, the results of gene profiling targeting 160 cancer-related genes in breast and non-breast cancer tissue were compared with the ERBB2-estimated gene copy number (CN).
Abstract: Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.
TL;DR: The use of melittin against peripheral neuropathy caused by chemotherapy has been limited despite having strong therapeutic efficacy against the disease as mentioned in this paper, however, there is a need to develop curative therapy that can be used to treat this complication.
Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of cancer treatment which involves sensory and motor nerve dysfunction. Severe CIPN has been reported in around 5% of patients treated with single and up to 38% of patients treated with multiple chemotherapeutic agents. Present medications available for CIPN are the use of opioids, nonsteroidal anti-inflammatory agents, and tricyclic antidepressants, which are only marginally effective in treating neuropathic symptoms. In reality, symptom reappears after these drugs are discontinued. The pathogenesis of CIPN has not been sufficiently recognized and methods for the prevention and treatment of CIPN remain vulnerable to therapeutic problems. It has witnessed that the present medicines available for the disease offer only symptomatic relief for the short term and have severe adverse side effects. There is no standard treatment protocol for preventing, reducing, and treating CIPN. Therefore, there is a need to develop curative therapy that can be used to treat this complication. Melittin is the main pharmacological active constituent of honeybee venom and has therapeutic values including in chemotherapeutic-induced peripheral neuropathy. It has been shown that melittin and whole honey bee venom are effective in treating paclitaxel and oxaliplatin-induced peripheral neuropathy. The use of melittin against peripheral neuropathy caused by chemotherapy has been limited despite having strong therapeutic efficacy against the disease. Melittin mediated haemolysis is the key reason to restrict its use. In our study, it is found that α-Crystallin (an eye lens protein) is capable of inhibiting melittin-induced haemolysis which gives hope of using an appropriate combination of melittin and α-Crystallin in the treatment of CIPN. The review summarizes the efforts made by different research groups to address the concern with melittin in the treatment of chemotherapeutic-induced neuropathy. It also focuses on the possible approaches to overcome melittin-induced haemolysis.
TL;DR: In this paper, the effect of lncRNA HIF1A-AS2 on autophagy-associated drug resistance in small cell lung cancer (SCLC) cells was determined by qRT-PCR analysis.
Abstract: The aim of this study was to determine the effect of lncRNA HIF1A-AS2 on autophagy-associated drug resistance in small cell lung cancer (SCLC) cells. The expression of HIF1A-AS2 was silenced by siRNA in doxorubicin-sensitive H69 and doxorubicin-resistant H69AR cells. Then, cytotoxicity, apoptosis and autophagy analyses were carried out in the normoxic and CoCl2-induced hypoxic environment. The effect of HIF1A-AS2 on the expression levels of genes, which are associated with drug resistance and autophagy, was determinated by qRT-PCR analysis. The levels of MRP1, HIF-1α and Beclin-1 were analyzed by western blot method. Knockdown of HIF1A-AS2 increased doxorubicin sensitivity of SCLC cells and decreased autophagy. Knockdown of HIF1A-AS2 has also affected the expression of several genes that will increase drug sensitivity and inhibit autophagy in both cell lines. The levels of HIF-1α and Beclin-1 were decreased in both cell lines by knockdown of HIF1A-AS2. MRP1 expression was decrease in H69AR cells. In addition, CoCl2-induced hypoxic environment decreased in doxorubicin sensitivity of H69 cells, and knockdown of HIF1A-AS2 reversed this effect of hypoxia. Knockdown of HIF1A-AS2 increased drug sensitivity of SCLC cells in relation to autophagy. Therefore, hypoxia-HIF1A-AS2-autophagy interaction is thought to be determinative in drug sensitivity of these cells.
TL;DR: Melittin suppresses the expression of genes responsible for formation of TME physiological hallmarks by suppressing HIF-1α signaling pathway, suggesting that Melittin can modulate tumor microenvironment by inhibition of VEGFA and LDHA.
Abstract: HIF-1α has critical roles in the formation of tumor microenvironment by regulating genes involved in angiogenesis and anaerobic respiration. TME fuels tumors' growth and metastasis and presents therapy with several challenges. Therefore, we aimed to investigate if Melittin disrupts HIF-1α signaling pathway in breast adenocarcinoma cell line MDA-MB-231. Breast adenocarcinoma cell line MDA-MB-231 was cultured in the presence of different doses of Melittin, and MTT assay was carried out to measure Melittin's cytotoxic effects. Cells were exposed to 5% O2 to mimic hypoxic conditions and Melittin. Western blot was used to measure HIF-1α protein levels. Gene expression analysis was performed using real-time PCR to measure relative mRNA abundance of genes involved in tumor microenvironment formation. Our results revealed that Melittin effectively inhibits HIF-1α at transcriptional and translational/post-translational level. HIF-1α protein and mRNA level were significantly decreased in Melittin-treated groups. It is found that inhibition of HIF-1α by Melittin is through downregulation of NFκB gene expression. Furthermore, gene expression analysis showed a downregulation in VEGFA and LDHA expression due to inhibition of HIF-1α protein by Melittin. In addition, cell toxicity assay showed that Melittin inhibits the growth of MDA-MB-231 cell line through activation of extrinsic and intrinsic apoptotic pathways by upregulating TNFA and BAX expression. Melittin suppresses the expression of genes responsible for formation of TME physiological hallmarks by suppressing HIF-1α signaling pathway. Our results suggest that Melittin can modulate tumor microenvironment by inhibition of VEGFA and LDHA.
TL;DR: In this paper, the influence of ballroom dancing on fatigue, body image, self-efficacy, and functional exercise capacity for patients with cancer was evaluated by collecting data among participants of a regular dance training program for cancer patients with a questionnaire including the Body Image Scale (BIS), Brief Fatigue inventory (BFI), Short Scale for Measuring General Self-efficity Beliefs (ASKU), and the 6min walking test (6-MWT).
Abstract: Physical activity has a high importance for cancer patients. The present study aimed to evaluate the influence of ballroom dancing on fatigue, body image, self-efficacy, and functional exercise capacity for patients with cancer. We collected data among participants of a regular dance training program for cancer patients with a questionnaire including the Body Image Scale (BIS), Brief Fatigue inventory (BFI), Short Scale for Measuring General Self-efficacy Beliefs (ASKU), and the 6-min walking test (6-MWT). 66 participants took part in the study, and among them, 39 participants also engaged in the 6-MWT: dance experience and the weeks of dance training were significantly associated with a higher walking distance in the 6-MWT. Participants with dance experience showed higher self-efficacy scores than participants without. Participants rated the influence of dancing on partnership positively. However, the dance training had no significant effects on fatigue or body image. Ballroom dancing may improve functional exercise capacity, and dance experience may be associated with a high self-efficacy and active lifestyle, which can be beneficial for cancer patients during and after treatment. Further studies are needed to assess the influence of ballroom dancing more deeply on physical activity and fitness and to learn more on impact on the partnership. As ballroom dancing seems to improve physical activity and wellbeing and can promote intimacy between partners, this intervention has the potential to support cancer survivors in various levels.
TL;DR: The involvement of KIFC1 in the progression of prostate cancer (PCa) is still not well understood as discussed by the authors, however, the involvement of kinesin family member C1 (KIFC1), a minus end-directed motor protein, is a novel Kinesin involved in the clustering of excess centrosomes found in cancer cells.
Abstract: Kinesins play important roles in the progression and development of cancer. Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is a novel Kinesin involved in the clustering of excess centrosomes found in cancer cells. Recently KIFC1 has shown to play a role in the progression of many different cancers, however, the involvement of KIFC1 in the progression of prostate cancer (PCa) is still not well understood. This study investigated the expression and clinical significance of KIFC1 in PCa by utilizing multiple publicly available datasets to analyze KIFC1 expression in patient samples. High KIFC1 expression was found to be associated with high Gleason score, high tumor stage, metastatic lesions, high ploidy levels, and lower recurrence-free survival. These results reveal that high KIFC1 levels are associated with a poor prognosis for PCa patients and could act as a prognostic indicator for PCa patients as well.
TL;DR: In this paper, the authors investigated the relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A/C and ATP7B rs9535828 A/G polymorphisms on the overall survival and disease free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated.
Abstract: The relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A > C and ATP7B (protein: P-type adenosine triphosphatase 7B) rs9535828 A > G polymorphisms on the overall survival and disease-free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated. Chemotherapy consisted of protracted infusion of 5-fluoracil (800 mg/m2/day) on days 1–5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. The median (range) follow-up was 47 (6–127) months. The 5-year overall and disease-free survival rates were 71.2% and 60.6%, respectively. The 5-year overall survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (91.7% vs. 65.0%, P = 0.018). The 5-year disease-free survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (79.2% vs. 55.0%, P = 0.043). In addition, univariate and multivariate analyses showed the SLC31A1 rs10981694 A > C polymorphism to be a significant prognostic factor affecting 5-year overall survival after neoadjuvant CRT. However, the overall and disease-free survival rates after surgery did not differ significantly among the ATP7B rs9535828 genotypes. In conclusion, only the SLC31A1 rs10981694 A/A genotype was an independent predictor of a poorer 5-year overall survival. Therefore, in neoadjuvant CRT for ESCC patients, the effect of platinum was affected by the SLC31A1 rs10981694 A > C polymorphism. The presence of this polymorphism should be considered when devising neoadjuvant CRT regimens or treatment strategies for ESCC.
TL;DR: This results demonstrate that this ex vivo PDCO model recapitulates the complexity of the epithelial tumor microenvironment of multifocal PC using orthogonal analyses and propose to leverage the Stacks microfluidic device as a high-throughput, translational platform to interrogate phenotypic and molecular endpoints with the capacity to incorporate a complex tumor micro environment.
Abstract: Prostate Cancer (PC) is a disease with remarkable tumor heterogeneity that often manifests in significant intra-patient variability with regards to clinical outcomes and treatment response. Commonly available PC cell lines do not accurately reflect the complexity of this disease and there is critical need for development of new models to recapitulate the intricate hierarchy of tumor pathogenesis. In current study, we established ex vivo primary patient-derived cancer organoid (PDCO) cultures from prostatectomy specimens of patients with locally advanced PC. We then performed a comprehensive multi-parameter characterization of the cellular composition utilizing a novel approach for live-cell staining and direct imaging in the integrated microfluidic Stacks device. Using orthogonal flow cytometry analysis, we demonstrate that primary PDCOs maintain distinct subsets of epithelial cells throughout culture and that these cells conserve expression of androgen receptor (AR)-related elements. Furthermore, to confirm the tumor-origin of the PDCOs we have analyzed the expression of PC-associated epigenetic biomarkers including promoter methylation of the GSTP1, RASSF1 and APC and RARb genes by employing a novel microfluidic rare-event screening protocol. These results demonstrate that this ex vivo PDCO model recapitulates the complexity of the epithelial tumor microenvironment of multifocal PC using orthogonal analyses. Furthermore, we propose to leverage the Stacks microfluidic device as a high-throughput, translational platform to interrogate phenotypic and molecular endpoints with the capacity to incorporate a complex tumor microenvironment.
TL;DR: In this paper, the mutational status of a cohort of 40 endometrial cancer patients, belonging to families with Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC), was determined.
Abstract: Endometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2–6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20–70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1, MSH2, BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2. Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2, c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.
TL;DR: In this paper, the efficacy of Lactobacillus plantarum and Candida albicans in the suppression of azoxymethane-induced colorectal cancer in male Fischer 344 rats was evaluated.
Abstract: The association of gut microbiota with occurrence and development of colorectal cancer (CRC) has been reported in recent studies. Probiotics have been shown to mediate anti-cancer effects through immune system. The aim of this study was to evaluate the efficacy of Lactobacillus plantarum and Candida albicans in the suppression of azoxymethane-induced CRC in male Fischer 344 rats. 30 adult male Fischer 344 rats were divided into 6 distinct groups (n = 5 per group): non-treated animals, fat-food intake group, fat-food and carcinogen intake group, CRC cancer-induced rats treated with the chemotherapy drug, CRC-induced rats treated with Lactobacillus plantarum, and CRC-induced rats treated with Candida albicans. Identification of Candida albicans isolated from human feces was performed by microbiological, biochemical, and PCR methods. The serum levels of IFN-γ, IL-4, TGF-β, and TNF-α were measured by ELISA. Pathological studies were performed through hematoxylin and eosin (H&E) staining method. The data were analyzed using one-way ANOVA and Tukey's post-hoc analysis. Shrinking cancer cells with very dark nuclei were observed in CRC-induced rats treated with the chemotherapy drug, Lactobacillus plantarum, and Candida albicans indicating the occurrence of apoptosis. Serum levels of IFN-γ, IL-4, and TGF-β significantly decreased compared to the control group (p < 0.05). Lactobacillus plantarum and Candida albicans isolated from the gastrointestinal tract of the elderly and healthy individuals can efficiently improve CRC.
TL;DR: In this paper, the authors performed a bioinformatics analysis concerning human melanoma tissues by the Gene Expression Omnibus (GEO) database and Gene Expression Profiling Interactive Analysis (GEPIA) platform.
Abstract: Melanoma is a high-grade malignant subtype of human skin cancer with the highest mortality rate. Here we perform a bioinformatics analysis concerning human melanoma tissues by the Gene Expression Omnibus (GEO) database and Gene Expression Profiling Interactive Analysis (GEPIA) platform. We found that lncRNA LINC01550 was significantly down-regulated in the melanoma tissues as compared to the normal tissues. The low expression of LINC01550 was tightly associated with shorter overall survival and disease-free survival of patients with melanoma. LINC01550 expression is negatively associated with tumor cell proliferation and invasion abilities in melanoma as evidenced by the single-cell RNA sequencing (scRNA-seq) databases. LINC01550-overexpressing vectors were transferred into melanoma cells (WM35 and WM451). Up-regulation of LINC01550 significantly inhibited proliferation and invasion abilities, as well as induced cell apoptosis and G1 and S phase arrest of the melanoma cells. In conclusion, overexpression of LINC01550 may serve as a potential therapeutic target for melanoma.
TL;DR: In this paper, the authors adopted an integrative analysis for the gene expression patterns of four microarray datasets in gene expression omnibus (GEO) and microRNAs (miRNAs) expression profiles.
Abstract: The third leading cause of cancer-related deaths in the world, colorectal cancer (CRC) is a global health issue that should be addressed in both diagnostics and therapeutics to improve patient survival rate. Today, microarray data analysis is increasingly being used as a novel and effective method for classification of malignancies and making prognostic assessments. Built upon the concept of microarray data analysis and aimed at the identification of CRC-associated genes, our study has adopted an integrative analysis for the gene expression patterns of four microarray datasets in gene expression omnibus (GEO) and microRNAs (miRNAs) expression profiles. We downloaded four gene expression profiles, i.e., GSE37182, GSE25070, GSE10950, and GSE113513, miRNAs gene expression profiles and differentially expressed genes (DEGs). We used R software, the DAVID database, protein-protein interaction (PPI) networks, the Cytoscape program and receiver operating characteristic (ROC) curve for data analysis. Out of the four gene expression profiles, a total of 43 common DEGs were identified, including 10 hub genes, SLC26A3, CLCA1, GUCA2A, MS4A12, CLCA4, GUCA2B, KRT20, AQP8, MAOA, and ADH1A, and four differentially expressed miRNAs, miR-552, miR-423-5p, miR-502-3p, and miR-490-5p. The highly enriched modes of the signaling pathways among these DEGs were speculated to be involved in various processes including nitrogen metabolism, mineral absorption, pancreatic secretions, and tyrosine metabolism in Kyoto encyclopedia of genes and genomes (KEGG) database. According to our bioinformatics analysis, the DEGs identified in the present study could be considered as significant hallmarks in the molecular mechanisms of CRC development. Our findings may assist scientists with developing novel strategies not only for prediction of CRC, but also for screening and early diagnosis, and treatment of CRC patients.
TL;DR: In this paper, a polyaneuploid cancer cell (PACC) appears to have higher lipid levels than the cancer cell from which they are derived, and it was shown that using the evolutionarily conserved roles of LDs to protect from cellular lipotoxicity allows PACCs to survive otherwise lethal stressors.
Abstract: Lipid droplets (LDs) are found throughout all phyla across the tree of life. Originating as pure energy stores in the most basic organisms, LDs have evolved to fill various roles as regulators of lipid metabolism, signaling, and trafficking. LDs have been noted in cancer cells and have shown to increase tumor aggressiveness and chemotherapy resistance. A certain transitory state of cancer cell, the polyaneuploid cancer cell (PACC), appears to have higher LD levels than the cancer cell from which they are derived. PACCs are postulated to be the mediators of metastasis and resistance in many different cancers. Utilizing the evolutionarily conserved roles of LDs to protect from cellular lipotoxicity allows PACCs to survive otherwise lethal stressors. By better understanding how LDs have evolved throughout different phyla we will identify opportunities to target LDs in PACCs to increase therapeutic efficiency in cancer cells.
TL;DR: In this article, a review of different action mechanisms of resveratrol related in the in vitro and in vivo studies using models of oral cancer is presented, where the authors discuss the different action mechanism of reserveratrol in both vitro and vivo studies.
Abstract: Oral cancer is a very common tumor worldwide with high incidence and mortality. The treatment of oral cancer involves surgery, radio- and chemotherapy; however, high failure rates and toxicity are noticed. Thus, the search of new drugs aiming a more effective treatment is welcomed. Natural products present chemopreventive and anti-cancer effects. Resveratrol is a naturally occurring antioxidant that contains several health benefits, including anti-inflammatory and antiproliferative activities. This review discusses the different action mechanisms of resveratrol related in the in vitro and in vivo studies using models of oral cancer.