Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation

Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated production and degradation of hyaluronan (HA), a major component of extracellular matrix involved in the malignant phenotype of cancer. In particular, increased hyaluronidase (HYAL) activity plays a critical role in cancer progression, at least in part, by producing low-molecular-weight- (LMW-) HA or small fragments of HA, suggesting HYAL as a target for cancer treatment. Hyaluromycin, a new member of the rubromycin family of antibiotics, was isolated from the culture extract of a marine-derived Streptomyces hyaluromycini as a HYAL inhibitor. We investigated the antitumor effects of hyaluromycin in PDAC cells. We examined the effects of hyaluromycin on the proliferation and migration of PDAC cells. To elucidate the mechanisms underlying the effect of hyaluromycin on PDAC cells, we examined the concentration of LMW-HA in the conditioned media after treating PDAC cells with hyaluromycin. We demonstrate that hyaluromycin inhibits proliferation and migration of PDAC cells. We also found that these antitumor effects of hyaluromycin were associated with a decreased concentration of LMW-HA and a decreased phosphorylation of ribosomal protein S6. Our results suggest that hyaluromycin is a promising new drug against this highly aggressive neoplasm

Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma.

BACKGROUND: Although pancreatic ductal adenocarcinoma is characterized by an abundant stroma enriched with hyaluronan (HA), the prognostic impact of HA and its regulators remains unknown. METHODS: Using immunohistochemistry, expression patterns of HA and its regulators, including a synthesizing enzyme (HAS2), and a degrading enzyme (HYAL1) were investigated in patients who received surgical resection. The prognostic significance of these markers and other clinicopathological variables was determined using univariate and multivariate analyses. The HA levels were determined quantitatively by enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that strong expressions of HA (P=0.008) and HAS2 (P=0.022) were significantly associated with shorter survival time after surgery. By contrast, weak expression of HYAL1 was significantly associated with poor survival (P=0.001). In multivariate analysis, tumor stage (hazard ratio (HR)=2.76, 95% confidence interval (CI): 1.14-6.66 P=0.024), strong HA expression (HR=6.04, 95%CI: 1.42-25.69 P=0.015), and weak HYAL1 expression (HR=3.16, 95%CI: 1.19-8.40 P=0.021) were independent factors predicting poor survival. ELISA revealed higher concentration of HA in pancreatic cancer tissues than in normal pancreatic tissues (P=0.001). CONCLUSION: These findings suggest, for the first time, that HA and its regulators may have prognostic impact in patients with pancreatic cancer

Immunohistochemical stainings of pancreatic cancer tissues with hyaluronan (HA), HAS2, and HYAL1.

<p>Stainings of HA, HAS2, and HYAL1 were found in the cytoplasm. (HA) Weak and strong HA staining patterns of tumor and stromal cells in pancreatic cancer. (HAS2) Weak and strong HAS2 staining patterns of tumor cells in pancreatic cancer. (HYAL1) Weak and strong HYAL1 staining patterns of tumor cells in pancreatic cancer. (Original magnification 200×).</p

Kaplan-Meier survival curves of patients according to the expression patterns of HA, HAS2, and

<p>HYAL1. Strong expressions of HA (P=0.008) and HAS2 (p=0.022) and weak expression of HYAL1 (p=0.001) were significantly associated with poor survival. </p

Changes in operative trends and short‐term outcomes of surgery for congenital biliary dilatation in adults using real‐world data: A multilevel analysis based on a nationwide administrative database in Japan

Abstract Aim We aimed to evaluate the operative trends and compare the short‐term outcomes between open and laparoscopic surgery for congenital biliary dilatation (CBD) in adults using real‐world data from Japan. Methods Data from the Japanese Diagnosis Procedure Combination database on 941 patients undergoing surgery for CBD at 357 hospitals from April 1, 2016, to March 31, 2021, were analyzed. The patients were divided into two groups: open surgery (n = 764) and laparoscopic surgery (n = 177). We performed a retrospective analysis via a multilevel analysis of the short‐term surgical outcomes and costs between open and laparoscopic surgery. Results The rate of laparoscopic surgery has been increasing annually and had almost doubled to 25% by 2021. There were no significant differences in the in‐hospital mortality rate or postoperative morbidity between the two groups. The length of anesthesia was significantly longer in the laparoscopic than open surgery group (8.80 vs 6.16 hours, p < .001). The time to removal of the abdominal drain and length of hospital stay were significantly shorter in the laparoscopic than open surgery group (6.12 vs 8.35 days, p = .001 and 13.57 vs 15.79 days, p < .001, respectively). The coefficient for cost was 463 235 yen (95% confidence interval, 289 679‐636 792) higher in laparoscopic than open surgery (p < .001). Conclusion The short‐term results were comparable between laparoscopic and open surgery for CBD. Further investigation is needed to validate our findings and long‐term outcomes