title: Prognostic Impact of Modulators of G proteins in Circulating Tumor Cells from Patients with Metastatic Colorectal Cancer.
abstract: The consequence of a loss of balance between G-protein activation and deactivation in cancers has been interrogated by studying infrequently occurring mutants of trimeric G-protein α-subunits and GPCRs. Prior studies on members of a newly identified family of non-receptor guanine nucleotide exchange factors (GEFs), GIV/Girdin, Daple, NUCB1 and NUCB2 have revealed that GPCR-independent hyperactivation of trimeric G proteins can fuel metastatic progression in a variety of cancers. Here we report that elevated expression of each GEF in circulating tumor cells (CTCs) isolated from the peripheral circulation of patients with metastatic colorectal cancer is associated with a shorter progression-free survival (PFS). The GEFs were stronger prognostic markers than two other markers of cancer progression, S100A4 and MACC1, and clustering of all GEFs together improved the prognostic accuracy of the individual family members; PFS was significantly lower in the high-GEFs versus the low-GEFs groups [H.R = 5, 20 (95% CI; 2,15-12,57)]. Because nucleotide exchange is the rate-limiting step in cyclical activation of G-proteins, the poor prognosis conferred by these GEFs in CTCs implies that hyperactivation of G-protein signaling by these GEFs is an important event during metastatic progression, and may be more frequently encountered than mutations in G-proteins and/or GPCRs.
authors.affiliation: Translational Laboratory, Medical Oncology Department, Complexo Hospitalario Universitario de Santiago de Compostela/SERGAS, Santiago de Compostela, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barbazan
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dunkel
authors.affiliation: Division of Biostatistics, Department of Family Medicine and Public Health, Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, TU München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, TU München, Munich, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Division of Biostatistics, Department of Family Medicine and Public Health, Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.|Division of Biostatistics, Department of Family Medicine and Public Health, Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000080866:Nucleobindins; D017434:Protein Structure, Tertiary; D000071999:S100 Calcium-Binding Protein A4 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C502451:CCDC88A protein, human; C580811:CCDC88C protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D044385:GTP-Binding Protein alpha Subunits; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C544162:MACC1 protein, human; D008840:Microfilament Proteins; C000630649:NUCB1 protein, human; C000630650:NUCB2 protein, human; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D000071999:S100 Calcium-Binding Protein A4; D015534:Trans-Activators; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; C077591:S100A4 protein, human