Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model.

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction.

Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion.

The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.

Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer.

Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P<0.05). We also found reduced tumor stroma and decreased proliferation of cancer cells in implanted cancer tissues with CD51-silenced PSCs (P<0.05). Our results showed that CD51 expression in pancreatic cancer stroma is associated with enhanced tumor malignancy and that CD51 may be a potential therapeutic target for pancreatic cancer.

Clinical experience of the modified nurse-assisted screening and psychiatric referral program.

OBJECTIVE: We previously reported that the nurse-assisted screening and psychiatric referral program (NASPRP) facilitated the psychiatric treatment of depressive patients, but the high refusal rate was a problem even though referral was recommended by the nurse to all positively screened patients. We modified the program so that the nurses could judge the final eligibility of referral using the result of the screening. This study assessed if the modified NASPRP led to more psychiatric referral of depressive patients. METHOD: We retrospectively evaluated the annual change of the psychiatric referral proportion and compared the findings among the usual care term, the NASPRP term, and the modified NASPRP terms. RESULTS: The referral proportions of the modified NASPRP terms were 4.4% and 3.9%. These were not significantly higher than the usual care term (2.5%), and significantly lower than the NASPRP term (11.5%). SIGNIFICANT OF RESULTS: The modified NASPRP did not facilitate psychiatric treatment of depressive patients and another approach is needed.

Can psychiatric intervention improve major depression in very near end-of-life cancer patients?

OBJECTIVE: Although depression is a prevalent and burdensome psychiatric problem in end-of-life cancer patients, little is known about its susceptibility to treatment, especially when patients reach very close to the end of life. This study was conducted to evaluate response rate of that end-of-life depression to psychiatric intervention and to assess the feasibility of conventional evidence-based pharmacological therapy for depression. METHODS: The medical records of 20 patients who were referred to the psychiatry division for major depressive disorder and died within 3 months after the referral were reviewed. The Clinical Global Impression-Improvement (CGI-I) Scale was used for each case, and responders were defined as patients whose scores were much or very much improved. All pharmacological treatments were extracted, and the doses of the antidepressant prescribed were compared to their evidence-based-defined therapeutic doses. RESULTS: Of the 20 patients, seven were responders, but no response was achieved when the survival time was less than 3 weeks. Most patients were treated with antidepressants, but the doses prescribed were far less than the defined doses, especially the doses of the tricyclic antidepreSsants (TCAs). SIGNIFICANCE OF RESULTS: These results suggested that patients' survival time largely determines susceptibility to psychiatric treatment, and it is hard to achieve response in patients whose survival time was less than about 1 month. Implementation of conventional evidence-based pharmacological treatment is difficult, especially with TCAs, and various antidepressants, which can be administrated by other routes, are needed when oral intake is impossible.