The secretome of colon cancer stem cells contains drug-metabolizing enzymes

• Published in: Journal of proteomics Vol. 91; pp. 84 - 96
• Main Authors: Emmink, Benjamin L, Verheem, André, Van Houdt, Winan J., Steller, Ernst J.A., Govaert, Klaas M., Pham, Thang V., Piersma, Sander R., Borel Rinkes, Inne H.M., Jimenez, Connie R., Kranenburg, Onno
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 08.10.2013
• Subjects: aldehyde dehydrogenase; Antineoplastic Agents - pharmacology; antioxidants; Antioxidants - chemistry; Antioxidants - metabolism; Bleomycin - pharmacology; Cancer stem cells; cell death; Cell Line, Tumor; Cell Separation; Cell Survival; cell viability; chemotherapy; Colonic Neoplasms - metabolism; Colorectal cancer; colorectal neoplasms; Computational Biology; Culture Media, Conditioned - chemistry; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacology; Drug resistance; Drug Resistance, Neoplasm; drugs; extracellular space; Gene Expression Regulation, Neoplastic; Humans; Mass-spectrometry; Neoplastic Stem Cells - metabolism; Oxidative Stress; Protein Folding; proteins; Proteome - metabolism; Proteomics; Recurrence; Secretome; stem cells; Secretome; Cancer stem cells; Drug resistance; Mass-spectrometry; Colorectal cancer
• ISSN: 1874-3919; 1876-7737
• DOI: 10.1016/j.jprot.2013.06.027

Drug-resistant cancer stem cells (CSCs) have been implicated in tumor recurrence following chemotherapy. However, the contribution of CSCs to drug-resistance in colorectal cancer is unclear and CSC-intrinsic drug-resistance mechanisms are ill-defined. Here, we address these issues by proteomic analysis of the secretomes of CSCs and isogenic differentiated tumor cells (DTCs) isolated from three distinct metastasized colon tumors. Mass spectrometry-based proteomics identified 1254 unique proteins in the conditioned media of the paired CSC and DTC cultures. Ingenuity Pathway Analysis revealed that proteins governing ‘Cell Death’ were most significantly enriched in the CSC secretome. The vast majority of these (37/43) promote cell survival. The CSC secretome is also characterized by a pro-survival Nrf2 antioxidant signature. Interestingly, proteome-maintenance networks are highly enriched in the CSC secretome. CSCs also secrete high levels of drug-metabolizing enzymes, including aldehyde dehydrogenase 1 (ALDH1A1) and bleomycin hydrolase (BLMH). We show that these enzymes cause extracellular detoxification of maphosphamide and bleomycin respectively. We conclude that colorectal CSCs are characterized by extensive survival and anti-oxidant networks, which are likely to contribute to CSC-intrinsic drug-resistance. In addition, CSCs may modulate drug responses in nearby tumor cells by detoxifying chemotherapeutic drugs in the extracellular space. Cancer stem cells are thought to play an important role in mediating drug resistance and tumor recurrence following chemotherapy. Therefore, it is important to identify the factors that are secreted by them. Our results provide novel insights into the pathways that govern the intrinsic resistance of CSCs to chemotherapy and, furthermore, demonstrate that they can also inactivate chemotherapeutic drugs in the extracellular space. A better understanding of the pathways that govern drug resistance in CSCs may help in developing effective CSC-targeting drugs. [Display omitted] •Secretome analysis of cancer stem cells and differentiated tumor cells•Survival proteins are enriched in the cancer stem cell secretome.•Cancer stem cells secrete high levels of drug-metabolizing enzymes.•Secreted drug-metabolizing enzymes detoxify drugs in the extracellular space.•Cancer stem cells may protect nearby non-CSCs from cytotoxic chemotherapy.