Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
| Autor: | John Lewicki, Andrew Lam, Michelle Stroud, Janak Raval, May Ji, Belinda Cancilla, Jie Wei, Fumiko Takada Axelrod, Gilbert O'Young, Wan-Ching Yen, Min Wang, Timothy Hoey, Ann M. Kapoun, Cecile Chartier, Cristina Dee-Hoskins, Austin L. Gurney, Pete Yeung, Shirley Ma, Christopher J. Bond, Jalpa Shah, Jennifer Cain, Marcus Fischer |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Mice SCID Biology medicine.disease_cause Bioinformatics 03 medical and health sciences Mice Mice Inbred NOD Cell Line Tumor Neoplasms medicine Animals Humans Molecular Targeted Therapy RSPO2 beta Catenin HEK 293 cells Wnt signaling pathway Cancer Antibodies Monoclonal medicine.disease Xenograft Model Antitumor Assays Wnt Proteins 030104 developmental biology HEK293 Cells Oncology Cancer cell Cancer research Signal transduction Stem cell Thrombospondins Signal Transduction |
| Zdroj: | Cancer research. 76(3) |
| ISSN: | 1538-7445 |
| Popis: | Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713–23. ©2015 AACR. |
| Databáze: | OpenAIRE |
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