Hajime Morohashi

4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells

Hyaluronan (HA) is a ubiquitous, major component of the pericellular matrix and is necessary for various physiological processes. It plays a very important role in biological barriers. We previously reported that 4-methylumbelliferone (MU) inhibits HA synthesis and pericellular HA matrix formation in cultured human skin fibroblasts, Streptococcus equi FM100, and B16F10 melanoma cells. We hypothesized that MU-mediated inhibition of HA synthesis and pericellular HA matrix formation would increase the efficacy of anticancer drugs. We have already demonstrated in vitro, using a sandwich binding protein assay and a particle exclusion assay, that MU inhibits HA synthesis and formation of the pericellular HA matrix, respectively, in human KP1-NL pancreatic cancer cells. AlamarBlue assay revealed that the anticancer effect of gemcitabine in KP1-NL cells was increased by pretreatment with MU. In vivo simultaneous administration of MU and gemcitabine to tumor-bearing mice with severe combined immunodeficiency disease (SCID) decreased the size of the primary and metastatic tumors more than did gemcitabine alone. These data strongly suggest that a combination of MU and gemcitabine is effective against human pancreatic cancer cells. MU may have potential as a chemosensitizer and may provide us with a new anticancer strategy.

Risk factor for permanent stoma and incontinence quality of life after sphincter-preserving surgery for low rectal cancer without a diverting stoma

The goal of the present study was to evaluate permanent stoma formation and defecation function in long‐term follow up after surgery for low rectal cancer without a diverting stoma. Subjects were 275 patients who underwent sphincter‐preserving surgery for low rectal cancer between 2000 and 2012. Clinical outcomes were evaluated and defecation function was assessed based on a questionnaire survey, using Wexner and modified fecal incontinence quality of life (mFIQL) scores. Incidence of anastomotic leakage was 21.8%, and surgery‐related death as a result of anastomotic leakage occurred in one male patient. Median follow‐up period was 4.9 years and permanent stoma formation rate was 16.7%. Anastomotic leakage was an independent predictor of permanent stoma formation (odds ratio [OR] 5.86, P<0.001). Age <65 years (OR 1.99, P=0.001) and male gender (OR 4.36, P=0.026) were independent predictors of anastomotic leakage. A permanent stoma was formed as a result of poor healing of anastomotic leakage in 29.6% of males, but in no females. Defecation function was surveyed in 27 and 116 patients with and without anastomotic leakage, respectively. These groups had no significant differences in median follow‐up period (63.5 vs 63 months), Wexner scores (quartile) (6 (2.5‐9) vs 6 (3‐11)), and mFIQL scores (26.1 (4.8‐64.2) vs 23.8 (5.9‐60.7). Defecation function associated with anastomotic leakage showed no significant dependence on gender or resection procedure. Sphincter‐preserving surgery without a diverting stoma may be indicated for females with low rectal cancer. In this procedure, male gender is a risk factor for anastomotic leakage and subsequent formation of a permanent stoma in one in three patients.

Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer

Myofibroblasts of colorectal cancer (CRC) have been associated with histopathological factors such as lymph node metastasis, liver metastasis and local recurrence. However, few studies have assessed the association between these malignant potentials and the myofibroblast distribution in CRC. We aimed to evaluate the relationship between clinical factors and myofibroblast distribution around CRC invasive lesions. The study included 121 cases of pT3 CRC that were diagnosed at stage II or III. Myofibroblast density of the following three histological layers was measured: the submucosa (SM), muscularis propria (MP) and subserosa (SS). We analyzed the relationship between the clinicopathological factors and myofibroblast density by studying the histopathological features of the three layers. The myofibroblast density of the MP layer was significantly higher in the groups with high-frequency lymphatic and venous invasion than the groups with low-frequency lymphatic (P<0.001) and venous (P<0.01) invasion, respectively. In the positive lymph node metastasis group, the myofibroblast density at the MP layer was significantly higher than that in the negative lymph node metastasis group (P<0.001). The high myofibroblast density group at the MP layer was significantly associated with poor overall survival (P<0.003). Our study indicated that myofibroblasts are a type of cancer-associated fibroblasts and that the myofibroblast distribution contributes to the malignant potential of CRC. Furthermore, we demonstrated that myofibroblasts present at the MP layer play an important role in the malignant potential and poor prognosis of patients with CRC.