title: Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation.
abstract: Cisplatin-based chemotherapeutic regimens are the most frequently used (neo)adjuvant treatments for the majority of solid tumors. While platinum-based chemotherapeutic regimens have proven effective against highly proliferative malignant tumors, significant relapse and progression rates as well as decreased overall survival are still observed. Currently, it is known that sub-populations of chemoresistant cells share biological properties with cancer stem cells (CSC), which are believed to be responsible for tumor relapse, invasion and ultimately disease dissemination through acquisition of mesenchymal cell traits. In spite of concentrated efforts devoted to decipher the mechanisms underlying CSC chemoresistance and to design targeted therapeutics to these cells, proteomics has failed to unveil molecular signatures capable of distinguishing between malignant and non-malignant stem cells. This has hampered substantial developments in this complex field. Envisaging a novel rationale for an effective therapy, the current review summarizes the main cellular and molecular mechanisms underlying cisplatin resistance and the impact of chemotherapy challenge in CSC selection and clinical outcome. It further emphasizes the growing amount of data supporting a role for protein glycosylation in drug resistance. The dynamic and context-dependent nature of protein glycosylation is also comprehensively discussed, hence highlighting its potentially important role as a biomarker of CSC. As the paradigm of cancer therapeutics shifts towards precision medicine and patient-tailored therapeutics, we bring into focus the need to introduce glycomics and glycoproteomics in holistic pan-omics models, in order to integrate diverse, multimodal and clinically relevant information towards more effective cancer therapeutics.
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Mass Spectrometry Center, QOPNA, Department of Chemistry of the University of Aveiro, Campus de Santiago, Aveiro, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Porto, Portugal. Electronic address: josealexandreferreira@ua.pt.
authors.forename: José Alexandre
authors.initials: JA
authors.lastname: Ferreira
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Peixoto
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Neves
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Gaiteiro
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal.
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
authors.affiliation: The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa Israel.
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.affiliation: Experimental Pathology and Therapeutics group, Portuguese Institute for Oncology of Porto, Porto, Portugal; Health School of University of Fernando Pessoa, Porto, Portugal; Department of Surgical Oncology, Portuguese Institute for Oncology, Porto, Portugal. Electronic address: llarasantos@gmail.com.
authors.forename: Lúcio Lara
authors.initials: LL
authors.lastname: Santos
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin
keywords: Cancer biomarkers; Cancer stem cells; Cancer therapy; Chemotherapy resistance; Cisplatin; Epithelial-to-mesenchymal; Protein glycosylation