CD90/Thy-1, a Cancer-Associated Cell Surface Signaling Molecule

CD90 is a membrane GPI-anchored protein with one Ig V-type superfamily domain that was initially described in mouse T cells. Besides the specific expression pattern and functions of CD90 that were described in normal tissues, i.e., neurons, fibroblasts and T cells, increasing evidences are currently highlighting the possible involvement of CD90 in cancer. This review first provides a brief overview on CD90 gene, mRNA and protein features and then describes the established links between CD90 and cancer. Finally, we report newly uncovered functional connections between CD90 and endoplasmic reticulum (ER) stress signaling and discuss their potential impact on cancer development

Protéostase cellulaire et tumeurs solides

Cellular proteostasis is the process regulating the production, folding, trafficking and degradation of proteins within the cell in order to maintain its homeostasis. Cellular proteostasis is frequently altered in tumor cells, leading to an accumulation of unfolded proteins. In response to this accumulation, the cell activates an adaptive physiological response called "Unfolded Protein Response" (UPR). In the first part of the study we showed that sorafenib, i.e. the standard of care for advanced hepatocellular carcinoma (HCC), altered tumor proteostasis and inhibited the initiation of protein translation. We looked for tools to measure the alteration of tumor proteostasis in patients by focusing on the regulation of serum tumor markers by cellular proteostasis. In the second part of the study, we explored a potential role of UPR in tumorigenesis of post-transplant renal cell carcinoma (RCC). The incidence of RCC is greatly increased in transplant patients compared to the general population. Although carcinogenesis of RCC is multifactorial, chronic intake of immunosuppressive drugs such as ciclosporin (CsA) appears to be involved in this process. We showed in vitro that CsA alters tumor proteostasis and induce UPR. This induction seemed linked to the aggressiveness of the RCC in this contextLa protéostase cellulaire représente l'ensemble des mécanismes régulant la production, le repliement, le transport et la dégradation des protéines dans la cellule afin de maintenir son homéostasie. La protéostase cellulaire est fréquemment altérée dans les cellules tumorales, pouvant induire une accumulation de protéines mal repliées. En réponse à cette accumulation, la cellule met en place une réponse physiologique adaptative appelée "Unfolded Protein Response" (UPR). Dans la 1ère partie de l'étude nous avons montré que le sorafénib, i.e. le traitement de référence du carcinome hépatocellulaire (CHC) avancé, altérait la protéostase tumorale et inhibait l'initiation de la traduction des protéines. Nous avons cherché des outils permettant de mesurer l'altération de la protéostase tumorale chez les patients en s'intéressant à la régulation des marqueurs tumoraux sériques par la protéostase cellulaire. Dans la deuxième partie de l'étude, nous avons exploré un potentiel rôle de l'UPR dans la tumorigénèse des carcinomes à cellules rénales (RCC) post-transplantation. L'incidence des RCC est largement augmentée chez les patients transplantés en comparaison à la population générale. Bien que la carcinogénèse du RCC soit multifactorielle, la prise chronique de traitements immunosuppresseurs tels que la ciclosporine (CsA) semble impliquée dans ce processus. Nous avons montré in vitro que la CsA pouvait altérer la protéostase tumorale et induire l'UPR. Cette induction semble liée à l'agressivité des RCC dans ce context

Cellular Proteostasis and Solid Tumors

La protéostase cellulaire représente l'ensemble des mécanismes régulant la production, le repliement, le transport et la dégradation des protéines dans la cellule afin de maintenir son homéostasie. La protéostase cellulaire est fréquemment altérée dans les cellules tumorales, pouvant induire une accumulation de protéines mal repliées. En réponse à cette accumulation, la cellule met en place une réponse physiologique adaptative appelée "Unfolded Protein Response" (UPR). Dans la 1ère partie de l'étude nous avons montré que le sorafénib, i.e. le traitement de référence du carcinome hépatocellulaire (CHC) avancé, altérait la protéostase tumorale et inhibait l'initiation de la traduction des protéines. Nous avons cherché des outils permettant de mesurer l'altération de la protéostase tumorale chez les patients en s'intéressant à la régulation des marqueurs tumoraux sériques par la protéostase cellulaire. Dans la deuxième partie de l'étude, nous avons exploré un potentiel rôle de l'UPR dans la tumorigénèse des carcinomes à cellules rénales (RCC) post-transplantation. L'incidence des RCC est largement augmentée chez les patients transplantés en comparaison à la population générale. Bien que la carcinogénèse du RCC soit multifactorielle, la prise chronique de traitements immunosuppresseurs tels que la ciclosporine (CsA) semble impliquée dans ce processus. Nous avons montré in vitro que la CsA pouvait altérer la protéostase tumorale et induire l'UPR. Cette induction semble liée à l'agressivité des RCC dans ce contexteCellular proteostasis is the process regulating the production, folding, trafficking and degradation of proteins within the cell in order to maintain its homeostasis. Cellular proteostasis is frequently altered in tumor cells, leading to an accumulation of unfolded proteins. In response to this accumulation, the cell activates an adaptive physiological response called "Unfolded Protein Response" (UPR). In the first part of the study we showed that sorafenib, i.e. the standard of care for advanced hepatocellular carcinoma (HCC), altered tumor proteostasis and inhibited the initiation of protein translation. We looked for tools to measure the alteration of tumor proteostasis in patients by focusing on the regulation of serum tumor markers by cellular proteostasis. In the second part of the study, we explored a potential role of UPR in tumorigenesis of post-transplant renal cell carcinoma (RCC). The incidence of RCC is greatly increased in transplant patients compared to the general population. Although carcinogenesis of RCC is multifactorial, chronic intake of immunosuppressive drugs such as ciclosporin (CsA) appears to be involved in this process. We showed in vitro that CsA alters tumor proteostasis and induce UPR. This induction seemed linked to the aggressiveness of the RCC in this contex

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

International audienceEndoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells' migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion

Relevance of blood tumor markers in inpatients with significant involuntary weight loss and elevated levels of inflammation biomarkers

International audiencePurpose To assess the diagnostic performance of a panel of standard tumor markers (TMs) in patients hospitalized with significant involuntary weight loss (IWL) and elevated levels of inflammation biomarkers, and a combination of the TM panel and the finding of the computed tomography (CT) scan. Methods We conducted a retrospective study in the internal medicine department at Amiens-Picardie University Medical Center (Amiens, France) between January 1st, 2015, and November 1st, 2021. The inclusion criteria were age 18 or over, significant IWL (≥ 5 kg over 6 months), elevated inflammation biomarkers (e.g. C-reactive protein), and assay data on two or more standard TMs (carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19 − 9, CA 15 − 3, CA 125, neuron-specific enolase (NSE), alpha-fetoprotein (AFP), calcitonin, and prostate-specific antigen (PSA)). The result of each TM assay was interpreted qualitatively (as positive or negative), according to our central laboratory’s usual thresholds. Results Cancer was diagnosed in 50 (37.0%) of the 135 patients included. Positivity for one or more TMs had a positive predictive value (PPV) of 0.55 [0.43–0.66], and a negative predictive value (NPV) of 0.84 [0.75–0.93] for cancer diagnosis. When combined with the presence of suspicious CT findings (e.g. a mass, enlarged lymph nodes and/or effusion), positivity for one or more TMs had a PPV of 0.92 [0.08–0.30]. In the absence of suspicious CT findings, a fully negative TM panel had an NPV of 0.96 [0.89-1.00]. Conclusion A negative TM panel argues against the presence of a cancer, especially in the absence of suspicious CT findings

Targeting the Unfolded Protein Response as a Potential Therapeutic Strategy in Renal Carcinoma Cells Exposed to Cyclosporine A

International audienceBackground/Aim: Organ transplant patients treated with the immunosuppressive drug cyclosporine A often present malignant kidney tumors. Cyclosporine A can promote oncogenesis in a cell-intrinsic manner by increasing the production of vascular endothelial growth factor (VEGF). Materials and Methods: We explored the impact of cyclosporine A and the role of the unfolded protein response (UPR) on three human renal cell carcinoma (RCC) cell lines under normoxic and hypoxic (1% O-2) conditions. Resullt:Cyclosporine A regulated the expression of VEGF at the post-transcriptional level. Cyclosporine A induced the inositol requiring enzyme-1 alpha (IRE1 alpha) arm of the UPR and stabilized neosynthesized proteins in RCC cells. Toyocamycin, an inhibitor of IRE1 alpha, abolished the clonogenic growth of RCC cells and reduced induction of VEGF by cyclosporine A under hypoxia. Conclusion: Our findings highlight the impact of cyclosporine A on the proteostasis of RCC cells, and suggest the potential therapeutic interest of targeting the UPR against tumors arising in the context of organ transplantation

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells can rely on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of novel IRE1 inhibitors identified through the structural exploration of the IRE1 kinase domain. We characterized the candidates in vitro and in cellular models and showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). We next selected a Blood-Brain Barrier (BBB) permeable inhibitor (Z4P) among these molecules and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. The hit compound disclosed in this study satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB

Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells

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A simple score (Biovid-19) based on biological parameters predicts transfer to intensive care units and death in COVID-19 patients

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A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

Summary: Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood–brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB