ABSTRACT
BACKGROUND: Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS: Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS: TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS: Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.
Subject(s)
Alternative Splicing , Annexin A2/metabolism , Biomarkers, Tumor/metabolism , Cell Membrane/metabolism , Pancreatic Neoplasms/pathology , Stromal Cells/metabolism , Tenascin/metabolism , Aged , Annexin A2/genetics , Biomarkers, Tumor/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Male , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/surgery , Prognosis , Protein Isoforms , Retrospective Studies , Survival Rate , Tenascin/geneticsABSTRACT
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer-associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)-6, IL-8, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cancer-Associated Fibroblasts/drug effects , Cytokines/metabolism , Pancreatic Neoplasms/prevention & control , Xenograft Model Antitumor Assays , Animals , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cytokines/genetics , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice, Inbred NOD , Mice, SCID , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Stellate Cells/drug effects , Pancreatic Stellate Cells/metabolism , Tumor Burden/drug effects , Tumor Burden/genetics , Vinca Alkaloids/administration & dosage , GemcitabineABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide. Stathmin 1 (STMN1) suppression was reported to reduce cellular viability and migration potential. However, no previous studies have addressed whether STMN1 overexpression is associated with malignant potential in PDAC. MATERIALS AND METHODS: To clarify the clinical significance of STMN1 in PDAC, the STMN1 expression in 104 PDAC samples was evaluated by immunohistochemistry. Moreover, we evaluated the proliferative potential and migration ability of pancreatic cancer cell line Suit2 cells highly expressing STMN1. RESULTS: Cytoplasmic STMN1 were higher levels in PDAC than in corresponding non-cancerous tissues. PDAC patients with high STMN1 (n=29) were significantly associated with poor differentiation and distant metastasis compared to those with low STMN1 (n=75). The proliferation rates and migration ability in Suit2-STMN1 were higher than those of Suit2-mock. CONCLUSION: STMN1 evaluation could be a useful progression marker, and STMN1 may be a promising candidate for targeted therapies in PDAC.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/secondary , Cell Differentiation , Cell Movement , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms/pathology , Stathmin/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Case-Control Studies , Cell Proliferation , Disease Progression , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymphatic Metastasis , Male , Middle Aged , Pancreas/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Prognosis , Stathmin/genetics , Tumor Cells, CulturedABSTRACT
Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer. FBXW7 expression was evaluated by immunohistochemistry in 122 pancreatic cancer tissues. Reduced FBXW7 expression was significantly associated with advanced venous invasion, high MCL1 expression, enhanced Ki-67 expression, and poor prognosis and was an independent poor prognostic factor. Among patients who underwent gemcitabine treatment after surgery, reduced FBXW7 expression was also significantly associated with poor prognosis. Knockdown of FBXW7 in vitro enhanced cell proliferation, and migration, and invasion abilities and promoted gemcitabine and nab-paclitaxel chemoresistance in pancreatic cancer cells. Moreover, FBXW7-knockdown cells showed accumulation of MCL1, and the enhanced chemoresistance observed in FBXW7-knockdown cells was eliminated by MCL1 suppression. These results suggested that FBXW7 was associated with cancer progression and mediated sensitivity to gemcitabine and nab-paclitaxel via MCL1 accumulation in pancreatic cancer. Thus, the FBXW7/MCL1 axis may be a promising therapeutic tool to overcome refractory pancreatic cancer.
