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EBioMedicine Jun 2024The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and...
BACKGROUND
The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport.
METHODS
To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of α-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer.
FINDINGS
Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer.
INTERPRETATION
We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer.
FUNDING
Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.
PubMed: 38889481
DOI: 10.1016/j.ebiom.2024.105178 -
Cancer Science Jun 2024Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality...
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
PubMed: 38889208
DOI: 10.1111/cas.16239 -
Frontiers in Endocrinology 2024Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated...
BACKGROUND
Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis.
METHODS
We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis.
RESULTS
After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, = 0.001, = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, = 0.0002, P = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, = 0.006).
CONCLUSION
Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.
Topics: Humans; Mendelian Randomization Analysis; Cathepsins; Neoplasms; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Female; Risk Factors
PubMed: 38883596
DOI: 10.3389/fendo.2024.1428433 -
F1000Research 2023Apocrine carcinoma is an extremely rare malignant cutaneous neoplasm that usually arises in areas with a high density of apocrine glands. Diagnosis can be challenging as...
Apocrine carcinoma is an extremely rare malignant cutaneous neoplasm that usually arises in areas with a high density of apocrine glands. Diagnosis can be challenging as tumours share histological and immunophenotypic characteristics with them. At first evaluation, the disease is often assumed to be benign. There have been approximately 100 reports of apocrine neoplasms in the literature. A 48-year-old male presented with a right axillary mass which increased in size over a period of 2 years. The patient was reported to have had ayurvedic therapy, but his swelling remained unchanged. Axillary lymph nodes were palpable. USG axilla suggested a well-defined fungating solid isoechoic lesion. USG neck did not reveal any abnormality. The mass was surgically excised as a whole by removing the overlying skin with margins and lymph node excision. The patient was diagnosed with primary apocrine carcinoma after surgical excision. The differentials include adenocarcinoma of breast and prostate and apocrine adenoma. There are no established standards for the care of this form of carcinoma due to its rarity and the absence of clinical studies. A literature evaluation and further reporting will aid in developing diagnostic standards and the most efficient treatment options.
Topics: Humans; Male; Middle Aged; Apocrine Glands; Sweat Gland Neoplasms; Skin Neoplasms; Diagnosis, Differential; Carcinoma
PubMed: 38882714
DOI: 10.12688/f1000research.135154.3 -
BMC Urology Jun 2024Carcinoma in situ of the bladder is a high-grade cancer that originates in the superficial layer of the bladder. It has the potential to invade nearby organs, and it can...
BACKGROUND
Carcinoma in situ of the bladder is a high-grade cancer that originates in the superficial layer of the bladder. It has the potential to invade nearby organs, and it can spread through blood and lymphatic circulation to distant parts of the body.
CASE PRESENTATION
A 58-year-old non-smoker male presented with gross and microscopic hematuria. His family history included his father's recent bladder cancer. Initial investigations showed hematuria, inflammation, negative urine culture, digital rectal examination revealed an enlarged right lobe of the prostate, and an elevated Prostate-Specific Antigen level. Histopathological examination of samples taken from the bladder mucosa and the prostate confirmed urothelial carcinoma in situ in the bladder and prostate. Further evaluation revealed no other metastasis. The tumor was classified as T4aN0M0. The patient underwent radical cystoprostatectomy and histopathological examination showed that the tumor invading the muscularis propria of the bladder as well as the prostatic glands, but no malignancy was found in prostatic urethra and other areas. The patient was discharged three weeks post-operation and completed on adjuvant chemotherapy consisting of Gemcitabine, and Cisplatin to prevent of relapse. The patient is currently in a good healthy.
CONCLUSION
The occurrence of bladder cancer metastasizing to the prostate without involving the prostatic urethra is uncommon and requires precise diagnostic techniques for accurate tumor classification. Early management is advised to enhance the prognosis for the patient.
Topics: Humans; Male; Middle Aged; Urinary Bladder Neoplasms; Prostatic Neoplasms; Carcinoma in Situ; Urethra
PubMed: 38879527
DOI: 10.1186/s12894-024-01516-6 -
American Society of Clinical Oncology... Jun 2024The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer... (Review)
Review
The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.
Topics: Humans; Carcinoma, Renal Cell; Immunotherapy; Kidney Neoplasms; Immune Checkpoint Inhibitors
PubMed: 38875505
DOI: 10.1200/EDBK_438658 -
PeerJ 2024Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. Phenethyl isothiocyanate (PEITC) is a bioactive substance present...
BACKGROUND
Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. Phenethyl isothiocyanate (PEITC) is a bioactive substance present primarily in the cruciferous vegetables. PEITC has exhibited anti-cancer properties in various cancers, including lung, bile duct, and prostate cancers. It has been demonstrated that PEITC can inhibit the proliferation, invasion, and metastasis of SK-Hep1 cells, while effectively inducing apoptosis and cell cycle arrest in HepG2 cells. However, knowledge of its anti-carcinogenic effects on Huh7.5.1 cells and its underlying mechanism remains elusive. In the present study, we aim to evaluate the anti-carcinogenic effects of PEITC on human HCC Huh7.5.1 cells.
METHODS
MTT assay and colony formation assay was performed to investigate the anti-proliferative effects of PEITC against Huh7.5.1 cells. The pro-apoptosis effects of PEITC were determined by Annexin V-FITC/PI double staining assay by flow cytometry (FCM), mitochondrial transmembrane potential (MMP) measurement, and Caspase-3 activity detection. A DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was conducted to estimate the DNA damage in Huh7.5.1 cells induced by PEITC. Cell cycle progression was determined by FCM. Transwell invasion assay and wound healing migration assay were performed to investigate the impact of PEITC on the migration and invasion of Huh7.5.1 cells. In addition, transcriptome sequencing and gene set enrichment analysis (GSEA) were used to explore the potential molecular mechanisms of the inhibitory effects of PEITC on HCC. Quantitative real-time PCR (qRT-PCR) analysis was performed to verify the transcriptome data.
RESULTS
MTT assay showed that treatment of Huh7.5.1 cells with PEITC resulted in a dose-dependent decrease in viability, and colony formation assay further confirmed its anti-proliferative effect. Furthermore, we found that PEITC could induce mitochondrial-related apoptotic responses, including a decrease of mitochondrial transmembrane potential, activation of Caspase-3 activity, and generation of intracellular reactive oxygen species. It was also observed that PEITC caused DNA damage and cell cycle arrest in the S-phase in Huh7.5.1 cells. In addition, the inhibitory effect of PEITC on the migration and invasion ability of Huh7.5.1 cells was assessed. Transcriptome sequencing analysis further suggested that PEITC could activate the typical MAPK, PI3K-Akt, and p53 signaling pathways, revealing the potential mechanism of PEITC in inhibiting the carcinogenic properties of Huh7.5.1 cells.
CONCLUSION
PEITC exhibits anti-carcinogenic activities against human HCC Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways. Our results suggest that PEITC may be useful for the anti-HCC treatment.
Topics: Humans; Isothiocyanates; Carcinoma, Hepatocellular; Liver Neoplasms; Proto-Oncogene Proteins c-akt; Cell Line, Tumor; Signal Transduction; Apoptosis; Cell Proliferation; Phosphatidylinositol 3-Kinases; Tumor Suppressor Protein p53
PubMed: 38873643
DOI: 10.7717/peerj.17532 -
BJUI Compass Jun 2024
PubMed: 38873347
DOI: 10.1002/bco2.324 -
Frontiers in Genetics 2024Cancer is a disease characterized by uncontrolled cellular growth where cancer cells take advantage of surrounding cellular populations to obtain resources and promote... (Review)
Review
Cancer is a disease characterized by uncontrolled cellular growth where cancer cells take advantage of surrounding cellular populations to obtain resources and promote invasion. Carcinomas are the most common type of cancer accounting for almost 90% of cancer cases. One of the major subtypes of carcinomas are adenocarcinomas, which originate from glandular cells that line certain internal organs. Cancers such as breast, prostate, lung, pancreas, colon, esophageal, kidney are often adenocarcinomas. Current treatment strategies include surgery, chemotherapy, radiation, targeted therapy, and more recently immunotherapy. However, patients with adenocarcinomas often develop resistance or recur after the first line of treatment. Understanding how networks of tumor cells interact with each other and the tumor microenvironment is crucial to avoid recurrence, resistance, and high-dose therapy toxicities. In this review, we explore how mathematical modeling tools from different disciplines can aid in the development of effective and personalized cancer treatment strategies. Here, we describe how concepts from the disciplines of ecology and evolution, economics, and control engineering have been applied to mathematically model cancer dynamics and enhance treatment strategies.
PubMed: 38873108
DOI: 10.3389/fgene.2024.1383676 -
Genome Medicine Jun 2024Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk...
BACKGROUND
Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population.
METHODS
To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRS). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants.
RESULTS
Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose-response effect of PRS on incident colorectal neoplasms. Incorporating PRS with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32).
CONCLUSIONS
Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.
Topics: Humans; Colorectal Neoplasms; Female; Early Detection of Cancer; Male; Middle Aged; Aged; Risk Assessment; Polymorphism, Single Nucleotide; Bayes Theorem; Risk Factors
PubMed: 38872215
DOI: 10.1186/s13073-024-01355-y