OPA3 overexpression modulates lipid droplet production and sensitizes colorectal cancer cells to bevacizumab treatment

Background:Colorectal cancer(CRC)represents a substantial risk to public health.Bevacizumab,thefirst US FDA-approved antiangiogenic drug(AAD)for human CRC treatment,faces resistance in patients.The role of lipid metabolism,particularly through OPA3-regulated lipid droplet production,in overcoming this resistance is under investigation.Methods:The protein expression pattern of OPA3 in CRC primary/normal tissues was evaluated by bioinformatics analysis.OPA3-overexpressed SW-480 and HCT-116 cell lines were established,and bevacizumab resistance and OPA3 effects on cell malignancy were examined.OPA3 protein/mRNA expression and lipid droplet-related genes were measured with Western blot and qRT-PCR.OPA3 subcellular localization was detected using immunofluorescence.Proliferation and apoptosis were assessed via colony formation andflow cytometry.Tube formation assays were conducted to assess the angiogenic potential of human umbilical vein endothelial cells(HUVECs).Lipid analysis was used to measure the phosphatidylcholine(PC)and lysophosphatidylcholine(LPC)levels in CRC cells.Results:Bioinformatics analysis revealed that OPA3 was downregulated in CRC.Overexpression of OPA3 inhibited CRC cell proliferation,stimulated apoptosis,and suppressed the angiogenic ability of HUVECs.OPA3 effectively reversed the resistance of CRC cells to bevacizumab and decreased lipid droplet production in CRC cells.Additionally,OPA3 reversed the bevacizumab-induced lipid droplet production in CRC cells,thereby increasing CRC cell sensitivity to bevacizumab treatment.Conclusion:This study suggests that OPA3 modulates lipid metabolism in CRC cells and reduces resistance to bevacizumab in CRC cells.Therefore,OPA3 may be a potential therapeutic target against the AAD resistance in CRC.

Vasculogenic mimicry:a pivotal mechanism contributing to drug resistance in antiangiogenic therapy

The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis have been developed.However,the clinical effectiveness of antiangiogenic therapy(AAT)in treating tumors has not lived up to expectations.In recent years,vasculogenic mimicry(VM)has attracted increasing attention from the academic community as a longstanding but often overlooked mechanism of nonangiogenic tumor vascularization.Within the tumor microenvironment,neoplastic cells can autonomously form vessel-like structures,creating a blood supply that does not rely on endothelial cells.This phenomenon,known as VM,is a critical marker of aggressive tumors and may play a significant role in conferring resistance to AAT.In this review,we thoroughly examine the evidence,clinical characteristics,and mechanisms of VM across various tumor types and explore its potential role and importance in resistance to AAT and the development of new antitumor therapies.

Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Immunotherapy for mucosal melanoma

Mucosal melanoma(MM)is extremely rare in Caucasians,whereas it is the second predominant melanoma subtype in Asian and other non-Caucasian populations.Distinct from cutaneous melanoma in terms of epidemiology,biology,and molecular characteristics,MM is characterized by more aggressive biological behavior,lower mutational burden,more chromosomal structure variants,and poorer prognosis.Because of the rarity of MM,its biological features are not fully understood,and potential novel therapies are less well depicted.Whereas immunotherapy has shown encouraging efficacy for cutaneous melanoma,its efficacy in MM is unclear due to limited sample sizes in clinical trials.Thus,in this review,we describe the epidemiological,clinical,and molecular features of MM and summarize the efficacies of different immunotherapies for MM,including immune checkpoint inhibitors,vaccines,oncolytic virus therapy,adoptive T-cell therapy,and various combination therapies.

Safety of endoscopy in patients undergoing treatments with antiangiogenic agents: A 5-year retrospective review

BACKGROUND Antiangiogenic agents(AAs)are increasingly used to treat malignant tumors and have been associated with gastrointestinal(GI)bleeding and perforation.Elective surgeries and endoscopy are recommended to be delayed for 31 d until after AAs treatment.Data regarding the safety of endoscopy while on antiangiogenic agents is extremely limited.No guidelines are in place to address the concern about withholding these anti-angiogenic drugs.AIM To evaluate the risks of endoscopy in patients on antiangiogenic agents from 2015 to 2020 at our institution.METHODS This is a single centered retrospective study approved by the institutional review board statement of the institution.Patients that underwent endoscopy within 28 d of antiangiogenic agents’treatment were included in the study.Primary outcome of interest was death,and secondary outcomes included perforation and GI bleeding.Data were analyzed utilizing descriptive statistics.Fifty-nine patients were included in the final analysis and a total of eighty-five procedures were performed that were characterized as low risk and high risk.RESULTS Among the 59 patients a total of 85 endoscopic procedures were performed with 24(28.2%)categorized as high-risk and 61(71.8%)procedures as low-risk.Of the total number of patients,(50%)were on bevacizumab and the rest were on imatinib(11.7%),lenvatinib(6.7%)and,ramucirumab(5%).The average duration between administration of AAs and the performance of endoscopic procedures was 9.9 d.No procedure-related adverse events were noted among our study population.We did observe two deaths with one patient,on lenvatinib for metastatic hepatocellular carcinoma,who had persistent bleeding despite esophageal variceal banding and died 4 d later from hemorrhagic shock.Another patient was diagnosed with acute myeloid leukemia died 24 d after an esophagogastroduodenoscopy with biopsy after transition to comfort care.CONCLUSION As per this single center retrospective study,the rate of endoscopic procedure-related adverse events and death within 28 d of AA administration appears to be low.

Efficacy and safety of thalidomide in patients with hepatocellular carcinoma

AIM: To evaluate which patients with hepatocellular carcinoma (HCC) are most likely to respond to thalidomide treatment. METHODS: From July 2002 to July 2004, patients with HCC who received thalidomide treatment, were enrolled. We extracted relevant data from the patients’ medical records, including history and type of hepatitis, comorbidity, serum α-fetoprotein (α-FP) level, volumetric changes in tumor, length of survival, and the dose, duration, side effects of thalidomide treatment. The tumor response was evaluated. On the basis of these data, the patients were divided into two groups: those with either partial response or stable disease (PR + SD group) and those with progressive disease (PD group). RESULTS: Two of 42 (5%) patients had a partial tumor response after treatment with thalidomide, 200 mg/d, and 9 (21%) had stable disease. Patients in the PR + SD group all had cirrhosis. Comparing patients with and without cirrhosis, the former were more likely to respond to thalidomide therapy (PR + SD: 100% vs PD: 64.5%, P = 0.041 < 0.05). Thalidomide was significantly more likely to be effective in tumors smaller than 5 cm (PR + SD: 63.6% vs PD: 25.8%, P = 0.034 < 0.05). Compared with patients with progressive disease (PD), patients in the PR + SD group had a higher total dose of thalidomide (13 669.4 ± 8446.0 mg vs 22 022.7 ± 11 461.4 mg, P = 0.023 < 0.05) and a longer survival (181.0 ± 107.1 d vs 304.4 ± 167.1 d, P = 0.047 < 0.05). Patients with comorbid disease had a significantly greater incidence of adverse reactions than those without (93.8% vs 60.0%, P = 0.021 < 0.05). The average number of adverse reactions in each person with a comorbid condition was twice as high as in those without other diseases (2.2 ± 1.3 vs 1.1 ± 1.2; P = 0.022 < 0.05). CONCLUSION: Thalidomide therapy is most likely to beeffective in patients with early stage small HCC, espe- cially in those with other underlying diseases. A low dose (200 mg/d) of thalidomide is recommended to continue the treatment long enough to make it more effective.

Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives

Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension(PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The Pub Med database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studie donly in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.

Efficacy and safety of ranibizumab for wet age-related macular degeneration in Chinese patients

AIM： To evaluate the clinical efficacy and safety of ranibizumab for wet age-related macular degeneration （wAMD） in Chinese patients and to determine the mean number of injections administered over one year of follow-up. METHODS： This single centre, retrospective observational case series study included data from 121 patients with wAMD （121 eyes） who were diagnosed by indirect ophthalmoscopy, fluorescence fundus angiography （FFA）, indocyanine green angiography, and optical coherence tomography. Ranibizumab was injected into the vitreous cavities once per month for 3mo and as needed afterwards. Changes in visual acuity and central foveal thickness （CFT） during the follow-up period were compared, and the mean number of injections over the year was calculated. Patients with one or more adverse events related to the drugs and injections were recorded for further adverse events analysis.RESULTS： The study population included 70 males and 51 females aged between 50 and 87y （mean： 71.32±9.41y）. The mean number of injections over the first year was 5±1 （range： 3-9）. The mean best-corrected visual acuity by Early Treatment Diabetic Retinopathy Study increased from 43.2±19.3 （95%CI： 39.8-46.7） at baseline to 51.7±20.1 （95%CI： 48.1-55.3）, and central foveal thickness （CFT） decreased from 526.5±277.0 μm （95%CI： 476.6-576.4） to 258.2±161.6 μm （95%CI： 229.2-287.3） at 12mo. The differences were statistically significant （P〈0.001）. Visual acuity significantly improved in 34.1% of the patients （38 eyes）, stabilized in 66.1% of the patients （80 eyes）, and significantly decreased in 2.5% of the patients （3 eyes）. CFT at baseline was an independent risk factor of decreased CFT and increased visual acuity. None of the patients had severe adverse events during the follow-up period.CONCLUSION： Ranibizumab can effectively control disease progression and improve visual acuity in patients with wAMD. The disease conditions of most patients stabilized after a one-year treatment with an average of 5 injections.

Angiogenesis of hepatocellular carcinoma: An immunohistochemistry study

BACKGROUND Although hepatocellular carcinoma(HCC) is one of the most vascular solid tumors, antiangiogenic therapy has not induced the expected results.AIM To uncover immunohistochemical(IHC) aspects of angiogenesis in HCC.METHODS A retrospective cohort study was performed and 50 cases of HCC were randomly selected. The angiogenesis particularities were evaluated based on the IHC markers Cyclooxygenase-2(COX-2), vascular endothelial growth factor(VEGF) A and the endothelial area(EA) was counted using the antibodies CD31 and CD105.RESULTS The angiogenic phenotype evaluated with VEGF-A was more expressed in small tumors without vascular invasion(pT1), whereas COX-2 was rather expressed in dedifferentiated tumors developed in non-cirrhotic liver. The CD31-related EA value decreased in parallel with increasing COX-2 intensity but was higher in HCC cases developed in patients with cirrhosis. The CD105-related EA was higher in tumors developed in patients without associated hepatitis.CONCLUSION In patients with HCC developed in cirrhosis, the newly formed vessels are rather immature and their genesis is mediated via VEGF. In patients with non-cirrhotic liver, COX-2 intensity and number of mature neoformed vessels increases in parallel with HCC dedifferentiation.

Computed tomography perfusion imaging as a potential imaging biomarker of colorectal cancer

Neovascularization was reported to arise early in the adenoma-carcinoma sequence in colorectal cancer(CRC),and the importance of angiogenesis in cancer progression has been established.Computed tomography(CT)perfusion(CTP)based on high temporal resolution CT images enables evaluation of hemodynamics of tissue in vivo by modeling tracer kinetics.CTP has been reported to characterize tumor angiogenesis,and to be a sensitive marker for predicting recurrence or survival in CRC.In this review,we will discuss the biomarker value of CTP in the management of CRC patients.

Antioxidant and antiangiogenic activities of the essential oils of Myristica fragrans and Morinda citrifolia

Objective:Toinvestigate the anti-angiogenic activity and antioxidant properties of Myristica fragrans（M.fragrans）（nutmeg） and Morinda citrifolia（M.citrifolia）（mengkudu） oils. Methods:The nutmeg and megkudu essential oils were obtained by steam distillation. The antioxidant activities of both essenlial oils were delermined by beta-carotene/ linoleic acid bleaching assay and reducing power while the anti-angiogenic activity was investigated using rat aortic ring assay using various concentrations.Results:The results showed that nutmeg oil has higher antioxidant activity than mengkudu oil.The nutmeg oil effectively inhibited the oxidation of linoleic acid with（88.68±0.1）%while the inhibition percentage of oxidation of linoleic acid of the mengkudu oil is（69.44±0.4）%.The nutmeg oil and mengkudu oil showed reducing power with an EC50 value of 181.4μg/mL and 3 043.0μg/mL,respectively.The anliangiogenic activity of nutmeg oil showed significant antiangiogenic activity with IC50 of 77.64μg/mL comparing to mengkudu oil which exhibits IC50 of 109.30μg/mL.Conclusion:Bioactive compound（s） will be isolated from the nutmeg essential oil to be developed as antiangiogenic drugs.

The 150 most important questions in cancer research and clinical oncology series:questions 57-66

Since the beginning of 2017,Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology,which sparkle diverse thoughts,interesting communications,and potential collaborations among researchers all over the world.In this article,10 more questions are presented as followed.Question 57.What are the major stresses that drive the formation,progression,and metastasis of a cancer? Question 58.What is the mechanism responsible for altering an acidic intracellular pH and a basic extracellular pH in normal tissue cells to a basic intracellular pH and an acidic extracellular pH in cancer cells,a fundamental and yet largely ignored phenomenon? Question 59.Where are the tumor-associated plasma microRNAs from in cancer patients? Question 60.Can we identify mechanisms employed by tumor subpopulations to evade standard therapies and seed relapse/metastatic tumors before treatment? Question 61.Why are mutation rates in epidermal growth factor receptor(EGFR) and erb-b2 receptor tyrosine kinase 2(ERBB2) higher in lung cancer from never smokers than that from smokers? Question 62.Does tumor vasculogenic mimicry contribute to the resistance against antiangiogenic therapy in renal cancer? Question 63.What molecular targeted drugs would be effective for non-clear cell renal cell carcinoma(RCC),especially metastatic papillary RCC and chromophobe RCC? Question 64.Can it be more effective by targeting both the vascular endothelial growth factor receptor(VEGFR) and MET signaling pathways in sporadic metastatic papillary renal cell carcinoma(RCC)? Question 65.What are the predictive biomarkers that may be used to identify the renal cell carcinoma(RCC) patients who can benefit from immune checkpoint inhibitor treatment? Question 66.How do we identify predictive molecular biomarkers to stratify clear cell renal cell carcinoma patients for targeted therapies?

The 150 most important questions in cancer research and clinical oncology series:questions 76-85

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology to promote cancer research and accelerate collaborations. In this article, 10 questions are presented as followed. Question 76. How to develop effective therapeutics for cancer cachexia? Question 77.How can we develop preclinical animal models to recapitulate clinical situations of cancer patients for more effective anti-cancer drug development? Question 78. How can we develop novel effective therapeutics for pancreatic cancer and hepatocellular carcinoma? Question 79. What are the true beneficial mechanisms of antiangiogenic therapy in cancer patients? Question 80. How to approach the complex mechanisms of interplay among various cellular and molecular components in the tumor microenvironment? Question 81. Can tissue oxygenation improve the efficacy of conventional chemotherapy on cancer? Question 82. Can tissue oxygenation improve the efficacy of radiotherapy on digestive system tumors including liver cancer? Question 83. Can we integrate metabolic priming into multimodal management of liver cancer? Question 84. Has the limit of anti-androgen strategy in prostate cancer treatment been reached by the new generation of anti-androgen drugs? Question 85. Can we identify individuals with early-stage cancers via analyzing their clinical and non-clinical information collected from social media, shopping history, and clinical, pathological, and molecular traces?

Chemical constituents from Munronia sinica and their bioactivities

Two new minor constituents,musinisins A(1)and B(2),together with five known compounds(3-7),were isolated from the aerial parts of Munronia sinica.Their structures were established by means of spectroscopic methods and the absolute stereochemistry of 1 was determined by single crystal X-ray experiment.Compound 4 showed antiangiogenic activity evaluated by a zebrafish model and apoptosis-inducing effect on A549 lung cancer cells.

Degarelix as a new antiangiogenic agent for metastatic colon cancer?

Recently,follicle stimulating hormone receptor was found to be selectively expressed by endothelial cells on tumor-associated blood vessels in a wide range of human cancers.In this context,we hypothesized that degarelix,a new gonadotropin-releasing hormone receptor antagonist developed for patients with prostate cancer,may have antiangiogenic effects via its capacity to block follicle stimulating hormone(FSH)production. We report the case of a patient with metastatic colon cancer exhibiting tumor progression after failure of all conventional chemotherapeutic regimens.The addition of degarelix to the last chemotherapeutic regimen was proposed as compassionate treatment.Degarelix induced a rapid decrease in FSH level.This treatment induced radiological stabilization and carcinoembryonic antigen stabilization during 1 year.Contrast-enhanced ultrasonography demonstrated reduction of tumor vas-clature.This case represents the first report of an antitumoral effect of degarelix in metastatic colon cancer and suggests an antiangiogenic property of this drug.

Disease control with sunitinib in advanced intrahepatic cholangiocarcinoma resistant to gemcitabine-oxaliplatin chemotherapy

Advanced cholangiocarcinoma is associated with poor prognostic survival and has limited therapeutic options available at present. The importance of angiogenesis and expression of pro-angiogenic factors in intrahepatic forms of cholangiocarcinoma suggest that therapies targeting angiogenesis might be useful for the treatment of this disease. Here we report three cases of patients with advanced intrahepatic cholangiocarcinoma progressive after standard chemotherapy and treated with sunitinib 50 mg/d in 6-wk cycles of 4 wk on treatment followed by 2 wk off treatment(Schedule 4/2). In all three patients, sunitinib treatment was associated with a sustained disease control superior to 4 mo, patients achieving either a partial response or stable disease. A reduction in tumor size and density was observed in all cases, suggesting tumor necrosis as a result of sunitinib treatment in these patients. In addition, sunitinib was generally well tolerated and the occurrence of side effects was managed with standard medical interventions, as required. Our results suggest that sunitinib therapy maybe associated with favorable outcomes and tolerability in patients with advanced cholangiocarcinoma. Those observations contributed to launch a prospective phase Ⅱ multicenter trial investigating sunitinib in advanced intrahepatic cholangiocarcinoma(SUN-CK study; NCT01718327).

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimi-zing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.

Comparisons of biophysical properties and bioactivities of mono-PEGylated endostatin and an endostatin analog

Background:Endostatin(ES) is a well-established potent endogenous antiangiogenic factor.An ES variant,called zinc-binding protein-ES(ZBP-ES),is clinically available;however,its use is limited by rapid renal clearance and short residence time.PEGylation has been exploited to overcome these shortcomings,and mono-PEGylated ES(called M_2ES) as well as mono-PEGylated ZBP-ES(MZBP-ES) are developed in our study.This study aimed to compare the biophysical properties and biological effects of M_2ES and MZBP-ES to evaluate their druggability.Methods:Circular dichroism and tryptophan emission fluorescence were used to monitor the conformational changes of M_2ES and MZBP-ES.Their resistance to trypsin digestion and guanidinium chloride(GdmCl)-induced unfolding was examined by Coomassie staining and tryptophan emission fluorescence,respectively.The biological effects of M_2ES and MZBP-ES on endothelial cell migration were evaluated using Transwell migration and wound healing assays,and the uptake of M_2ES and MZBP-ES in endothelial cells was also compared by Western blotting and immunofluorescence.Results:Structural analyses revealed that M_2ES has a more compact tertiary structure than MZBP-ES.Moreover,M_2ES was more resistant to trypsin digestion and GdmCI-induced unfolding compared with MZBP-ES.In addition,although M_2ES and MZBP-ES showed comparable levels of inhibiting transwell migration and wound healing of endothelial cells,M_2ES displayed an increased ability to enter cells compared with MZBP-ES,possibly caused by the enhanced interaction with nucleolin.Conclusions:M_2ES has a more compact tertiary structure,is more stable for trypsin digestion and GdmCI-induced unfolding,exhibits increased cellular uptake and shows equivalent inhibitory effects on cell migration relative to MZBP-ES,indicating that M_2ES is a more promising candidate for anticancer drug development compared with MZBP-ES.

Multiline treatment of advanced squamous cell carcinoma of the lung: A case report and review of the literature

BACKGROUND Squamous cell carcinoma (SCC) is one the most common subtypes of non-small cell lung cancer, yet the treatment options for it remain limited. Here, we report a case of advanced SCC and review the related literature focusing on the multiline therapy method. CASE SUMMARY We report the case of a 45-year-old man with advanced SCC who was deemed inoperable at the time of advanced SCC diagnosis. The patient had been referred to our hospital in April 2013 with complaints of a stuffy feeling in the chest, dyspnea, and pain in the right shoulder lasting for 1 mo. Physical examination found no obvious abnormalities, except for lower breath sound in the right lower lung. Laboratory data were within normal limits. Immunohistochemistry analysis of the tumor tissue showed CK5/6 (+), p63 (+), CD56 (+), and Ki-67 (+, approximately 30%), and genetic testing detected no EGFR mutation. He received a multiline treatment that included chemotherapy, radiotherapy, targeted therapy, and antiangiogenic therapy. After more than 5-year comprehensive treatment, the patient remains alive. CONCLUSION This typical case highlights the importance of appropriate multiline therapy for those patients with advanced SCC.

Synthesis of Some Potential Antiangiogenic 1,3-Dihydro-1,3-dioxo-2H-isoindole Derivatives

Based on the structure-activity relationships of RGD-containing peptides, a series of 1,3-dihydro-1,3-dioxo-2H-isoindole derivatives were synthesized. All of them were first reported. Their structures were confirmed by spectral data and elemental analysis. Their ability to inhibit angiogenesis were evaluated in the chick embryo chorioallantoic membrane assay at 10-5 mol/L. Compounds 5b and 5e displayed obviously antiangiogenic activity.