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Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.

We tested the association between endogenous testosterone density (ETD; the ratio between endogenous testosterone [ET] and prostate volume) and prostate cancer (PCa) aggressiveness in very favorable low- and intermediate-risk PCa patients who underwent radical prostatectomy (RP). Only patients with prostate-specific antigen (PSA) within 10 ng ml−1, clinical stage T1c, and International Society of Urological Pathology (ISUP) grade group 1 or 2 were included. Preoperative ET levels up to 350 ng dl−1 were classified as abnormal. Tumor quantitation density factors were evaluated as the ratio between percentage of biopsy-positive cores and prostate volume (biopsy-positive cores density, BPCD) and the ratio between percentage of cancer invasion at final pathology and prostate weight (tumor load density, TLD). Disease upgrading was coded as ISUP grade group >2, and progression as recurrence (biochemical and/or local and/or distant). Risk associations were evaluated by multivariable Cox and logistic regression models. Of 320 patients, 151 (47.2%) had intermediate-risk PCa. ET (median: 402.3 ng dl−1) resulted abnormal in 111 (34.7%) cases (median ETD: 9.8 ng dl−1 ml−1). Upgrading and progression occurred in 109 (34.1%) and 32 (10.6%) cases, respectively. Progression was predicted by ISUP grade group 2 (hazard ratio [HR]: 2.290; P = 0.029) and upgrading (HR: 3.098; P = 0.003), which was associated with ISUP grade group 2 (odds ratio [OR]: 1.785; P = 0.017) and TLD above the median (OR: 2.261; P = 0.001). After adjustment for PSA density and body mass index (BMI), ETD above the median was positively associated with BPCD (OR: 3.404; P < 0.001) and TLD (OR: 5.238; P < 0.001). Notably, subjects with abnormal ET were more likely to have higher BPCD (OR: 5.566; P = 0.002), as well as TLD (OR: 14.998; P = 0.016). Independently by routinely evaluated factors, as ETD increased, BPCD and TLD increased, but increments were higher for abnormal ET levels. In very favorable cohorts, ETD may further stratify the risk of aggressive PCa.

The LPP family is comprised of three enzymes that dephosphorylate bioactive lipid phosphates both intracellularly and extracellularly. Pre-clinical breast cancer models have demonstrated that decreased LPP1/3 with increased LPP2 expression correlates to tumorigenesis. This though has not been well verified in human specimens. In this study, we correlate LPP expression data to clinical outcomes in over 5000 breast cancers from three independent cohorts (TCGA, METABRIC, and GSE96058), investigate biological function using gene set enrichment analysis (GSEA) and the xCell cell-type enrichment analysis, and confirm sources of LPP production in the tumor microenvironment (TME) using single-cell RNA-sequencing (scRNAseq) data. Decreased LPP1/3 and increased LPP2 expression correlated to increased tumor grade, proliferation, and tumor mutational burden (all p < 0.001), as well as worse overall survival (hazard ratios 1.3–1.5). Further, cytolytic activity was decreased, consistent with immune system invasion. GSEA data demonstrated multiple increased inflammatory signaling, survival, stemness, and cell signaling pathways with this phenotype across all three cohorts. scRNAseq and the xCell algorithm demonstrated that most tumor LPP1/3 was expressed by endothelial cells and tumor-associated fibroblasts and LPP2 by cancer cells (all p < 0.01). Restoring the balance in LPP expression levels, particularly through LPP2 inhibition, could represent novel adjuvant therapeutic options in breast cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and rapidly progresses. The overall response rate of PDAC to current treatment methods is still unsatisfactory. Thus, identifying novel targets and clarifying the underlying mechanisms associated with PDAC progression may potentially offer additional treatment strategies. AHNAK2 is aberrantly expressed in a variety of tumors and exerts pro-tumorigenic effects. However, the biological role of AHNAK2 in PDAC remains poorly understood. The expression of AHNAK2 in PDAC and paired non-tumor tissues was detected by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). Lentivirus knockdown was performed to investigate the impact of AHNAK2 on the biological function of pancreatic cancer cells. The subcutaneous cell-derived xenograft (CDX) model and the KPC spontaneous mouse model with AHNAK2 silencing were used to observe the effects of AHNAK2 on tumor growth and prognosis. The expression of c-MET at protein level in response to HGF treatment was assessed using western blot. Our results demonstrated that AHNAK2 was highly expressed in PDAC clinical samples and associated with poor prognosis. Knockdown of AHNAK2 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells. AHNAK2 knockdown or knockout resulted in tumor growth suppression and prolonged survival in mice with PDAC. In addition, AHNAK2 and c-MET expression levels showed a significant positive correlation at the post-transcriptional level. Mechanistically, AHNAK2 promoted tumor progression by preventing c-MET degradation and persistently activating the HGF/c-MET signaling pathway. Overall, our study revealed that AHNAK2 plays an important role in PDAC progression by modulating the c-MET signaling pathway, and targeting AHNAK2 may be an effective therapeutic strategy for PDAC.

PurposeIn percutaneous ablation procedures, periprocedural pain, unrest and respiratory concerns can be detrimental to achieve a safe and efficacious ablation and impair treatment outcome. This study aimed to compare the association between anesthetic technique and local disease control in patients undergoing percutaneous microwave ablation (MWA) of colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC).Materials and MethodsThis IRB-exempted single-center comparative, retrospective analysis of three cohorts analyzed 90 patients treated for hepatic malignancies from January 2013 until September 2018. The local tumor progression-free survival (LTPFS), safety and periprocedural pain perception were assessed using univariate and multivariate Cox proportional hazard regression analyses to correct for potential confounders.ResultsIn 114 procedures (22 general anesthesia; 32 midazolam; 60 propofol), 171 liver tumors (136 CRLM; 35 HCC) were treated with percutaneous MWA. Propofol and general anesthesia were superior to midazolam/fentanyl sedation regarding LTPFS (4/94 [4.3%] vs. 19/42 [45.2%] vs. 2/35 [5.7%]; P < 0.001, respectively). Local tumor progression rate was 14.6% (25/171). Eighteen tumors (72.0%) were retreated by ablation. Of them, 14 (78%) were previously treated with midazolam. Propofol versus midazolam (P < 0.001), general anesthesia versus midazolam (P = 0.016), direct postprocedural visual analog pain score above 5 (P = 0.050) and more than one tumor per procedure (P = 0.045) were predictors for LTPFS. Multivariate analysis revealed that propofol versus midazolam (HR 7.94 [95% CI 0.04–0.39; P < 0.001]) and general anesthesia versus midazolam (HR 6.33 [95% CI 0.04–0.69; P = 0.014]) were associated with LTPFS. Pain during and directly after treatment was significantly worse in patients who received midazolam sedation (P < 0.001).ConclusionsCompared to propofol and general anesthesia, midazolam/fentanyl sedation was associated with an increased periprocedural perception of pain and lower local tumor progression-free survival. To reduce the number of repeat procedures required to eradicate hepatic malignancies, general anesthesia and propofol sedation should be favored over midazolam.

ABSTRACT Background Radiofrequency ablation (RFA) is a curative treatment for colorectal liver metastases (CLMs) in selected patients. NCCN guidelines recommend RFA for both unresectable and select resectable CLMs when complete ablation with adequate margins is feasible. While RFA can achieve oncologic outcomes comparable to surgery in well‐selected patients, residual tumors are associated with a poorer prognosis. Objectives To identify predictors of residual tumor after percutaneous RFA for CLMs and evaluate their impact on overall survival (OS) and new intrahepatic metastases (NIHM). Methods We prospectively included patients with CLMs who underwent percutaneous RFA from November 2019 to November 2022. Dynamic contrast‐enhanced computed tomography assessed CLMs before and after RFA. Residual tumor was defined as active tumor visible immediately post‐ablation or within 4–8 weeks, within 1 cm of the ablation zone. Data from three centers formed a developmental cohort, validated with patients from a fourth center. Cox regression and Kaplan–Meier analysis assessed local tumor progression‐free survival (LTPFS), NIHM, and OS. Results Among 200 patients (mean age 61 years, 126 men) with 410 tumors, independent predictors of residual tumors included perivascular tumor location (odds ratio [OR] = 6.673), tumor size ≥ 20 mm (OR = 3.925), and minimal ablative margin (OR = 0.599). These factors also predicted LTPFS. NIHM was more frequent in the residual tumor group than in the complete RFA (cRFA) group (p = 0.002). Median OS was 45 months, shorter in the residual tumor group (30 vs. 48 months, p = 0.009). Patients with NIHM who received transarterial chemoembolization combined with hepatic arterial infusion chemotherapy had a median OS of 43 months, compared to 34 months with RFA alone (p = 0.039). Conclusions A non‐perivascular tumor location, tumor size < 20 mm, and a sufficient ablation margin are essential for achieving complete RFA. Residual tumors are associated with increased NIHM and shorter OS.

Background: Long intergenic noncoding RNA regulator of reprogramming (linc-ROR) is a novel long noncoding RNA that exhibits significant effects on cancer progression. This research presented that linc-ROR had a crucial part in promoting biological characteristics associated with worse prognosis in colon cancer. Method: Bioinformatics analysis was performed to predict signaling pathways related to linc-ROR. In addition, western blot, quantitative reverse transcription-polymerase chain reaction, RNA-pulldown, cell proliferation assays, colony formation assays, wound healing assays, and transwell assays were applied to detect the role and regulation of particular molecules. Results: Our results showed that the knockdown of linc-ROR reduced cell invasion, proliferative ability, and migration in colon cancer. Further evaluation verified that downregulating linc-ROR inhibited the activation of epidermal growth factor receptor (EGFR) signaling. In addition, cbl-b, a kind of E3 ubiquitin ligase that increases the degradation of EGFR, was found to be a potential linc-ROR target. Conclusions: Based on our findings, it was presented that linc-ROR served a role as a tumor-promoting factor via repressing the ubiquitination and degradation of EGFR signaling, which indicated that it could be a possible prognostic marker and therapeutic target for colon cancer.

Objectives The time for posttreatment tumor progression differs between nasopharyngeal carcinoma (NPC) patients. Herein, we established effective nomograms for predicting early tumor progression (ETP) and late tumor progression (LTP) in NPC patients. Methods We retrospectively enrolled 8292 NPC patients (training cohort: n = 6219; validation cohort: n = 2073). The ELP and LTP were defined as the time to tumor progression ≤24 and >24 months after treatment, respectively. Results The ETP and LTP accounted for 52.6 and 47.4% of the total patient cohort, respectively. Patients who developed ETP had markedly worse overall survival (OS) versus patients who suffered from LTP (5‐year OS: 26.2% vs. 59.7%, p < 0.001). Further, we identified 10/6 predictive factors significantly associated with ETP/LTP via logistic regression analyses. These indicators were used separately to construct two predictive nomograms for ETP and LTP. In the training group, the ETP nomogram [Harrell Concordance Index (C‐index) value: 0.711 vs. 0.618; p < 0.001] and LTP nomogram (C‐index value: 0.701 vs. 0.612; p < 0.001) were significantly superior for risk stratification than the TNM staging. These results were supported in the validation group with a C‐index value of 0.753 and 0.738 for the ETP and LTP nomograms, respectively. High‐risk patients defined by ETP/LTP nomograms had shorter progression‐free survival than low‐risk patients (all p < 0.001). Conclusion The established nomograms can help in ELP or LTP risk stratification for NPC patients. Our current results might also provide insights into individualized treatment decisions and designing surveillance strategies for NPC patients. We successfully constructed and validated two nomograms to facilitate early tumor progression (ETP) and late tumor progression (LEP) risk stratification for NPC patients. The ETP and LTP nomograms demonstrated that the high‐isk group had a shorter progression‐free survival (PFS) than the low‐risk group. Moreover, this study facilitated the prediction of ETP or LTP risk, which might also provide valuable insights into treatment decisions and designing surveillance strategies for NPC after definitive treatment.

Background Programmed death ligand‐1 (PD‐L1) has a known association with the prognosis of human cancers because of its ability to alter tumor immune surveillance via its interaction with PD‐1. We questioned whether expression of PD‐L1 in tumor cells could directly promote tumor growth and invasiveness in non–small cell lung cancer (NSCLC). Methods Real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) was performed to evaluate PD‐L1 messenger RNA (mRNA) expression in lung tumors. The prognostic value of PD‐L1 mRNA was assessed by Cox regression model. Transcriptional regulation of PD‐L1 by human papillomavirus (HPV) 16/18 E6 oncoprotein or by epidermal growth factor receptor (EGFR) mutation in lung cancer cells was examined by Western blot and luciferase reporter assay. The cell growth and invasion were evaluated by colony formation, soft agar growth, and Boyden chamber assay. Results The PD‐L1 mRNA levels showed a positive association with HPV 16/18 E6 oncoprotein and with EGFR mutation in 223 surgically resected NSCLC patients. The prognostic significance of PD‐L1 was more commonly observed in patients with high PD‐L1/E6 positive and high PD‐L1/EGFR mutant tumors. Mechanistically, upregulation of PD‐L1 transcription by E6 or mutant EGFR occurred largely through the ERK‐C/EBPβ‐TLR4‐NF‐κB cascade. PD‐L1 promotes the efficacy of colony formation, soft agar growth, and cell invasion. PD‐L1 upregulates BAG‐1 to reduce transforming growth factor (TGF)‐β1 expression, and the decrease in SMAD4 because of TGF‐β1 occurs through the p53/microRNA (miR)‐224 axis. The decreases in TGF‐β1 and SMAD4 are responsible for PD‐L1‐mediated cell invasiveness. Conclusion Induction of PD‐L1 by E6 oncoprotein or mutant EGFR through the ERK‐C/EBPβ‐TLR4‐NF‐κB cascade may promote tumor growth and invasiveness in NSCLC because of decreasing TGF‐β1 and SMAD4 expression. Induction of PD‐L1 by E6 oncoprotein or mutant EGFR through the ERK‐C/EBPβ‐TLR4‐NF‐κB cascade may promote tumor growth and invasiveness in NSCLC because of decreasing TGF‐β1 and SMAD4 expression. Therefore, we suggest anti‐PD‐L1 immunotherapy combined with MEK/ERK inhibitors might show a clinical benefit as a treatment for NSCLC, particularly in patients with E6‐positive and/or EGFR mutant tumors.

Heme oxygenase (HO-1) plays an important role in cellular protection against various stresses. The induction of HO-1 is an effective strategy for reactive oxygen species-related diseases, inflammatory diseases, as well as suppressing carcinogenesis. On the other hand, the high expression of HO-1 is now well known in many tumors. In this study, we investigated the dynamics of HO-1 expression in the host and the tumor. In the mouse sarcoma S180 solid tumor model and the rat hepatoma AH136B ascitic tumor model, HO-1 expression in the tumor, as indicated by the end product of HO-1 activation, i.e., carbon monoxide, gradually increased along with tumor growth. Over-expression of HO-1 expression in mouse colon cancer C26 tumor cells significantly promoted tumor growth as well as lung metastasis, whereas opposite results were found when the HO-1 expression was reduced in the cells. On the other hand, upregulating HO-1 levels in the host by using an HO-1 inducer protected the progression of the xenograft tumor in mice, whereas lowering HO-1 expression in the host with an HO-1 inhibitor showed accelerated tumor growth and lung metastasis after subcutaneous tumor xenograft inoculation. These findings strongly suggest that the balance of HO-1 levels in the host and the tumor cells is essential for the occurrence, progression, and prognosis of cancer. Maintenance of appropriately high HO-1 levels in the host is favorable for cancer prevention, whereas suppression of HO-1 in the tumor cells may thus become a therapeutic strategy for cancer.