scholarly journals Collagen Type XI Alpha 1 (COL11A1): A Novel Biomarker and a Key Player in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 935
Author(s):  
Sameera Nallanthighal ◽  
James Patrick Heiserman ◽  
Dong-Joo Cheon
Keyword(s):  
Collagen Fiber ◽  
Collagen Type ◽  
Bone Development ◽  
Tumor Stroma ◽  
Therapy Resistance ◽  
Metabolic Phenotype ◽  
Fiber Assembly ◽  
Survival Pathways ◽  
Type Xi Collagen

Collagen type XI alpha 1 (COL11A1), one of the three alpha chains of type XI collagen, is crucial for bone development and collagen fiber assembly. Interestingly, COL11A1 expression is increased in several cancers and high levels of COL11A1 are often associated with poor survival, chemoresistance, and recurrence. This review will discuss the recent discoveries in the biological functions of COL11A1 in cancer. COL11A1 is predominantly expressed and secreted by a subset of cancer-associated fibroblasts, modulating tumor-stroma interaction and mechanical properties of extracellular matrix. COL11A1 also promotes cancer cell migration, metastasis, and therapy resistance by activating pro-survival pathways and modulating tumor metabolic phenotype. Several inhibitors that are currently being tested in clinical trials for cancer or used in clinic for other diseases, can be potentially used to target COL11A1 signaling. Collectively, this review underscores the role of COL11A1 as a promising biomarker and a key player in cancer.

scholarly journals Chemotherapy resistance and stromal targets in breast cancer treatment: a review

2020 ◽  
Vol 47 (10) ◽  
pp. 8169-8177
Author(s):  
Y. M. van der Spek ◽  
J. R. Kroep ◽  
R. A. E. M. Tollenaar ◽  
Wilma E. Mesker
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Chemotherapy Resistance ◽  
Tumor Stroma ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Specific Therapy ◽  
Primary Tumors ◽  
Cytokines And Chemokines

Abstract Therapy resistance is a known problem in breast cancer and is associated with a variety of mechanisms. The role of the tumor microenvironment in cancer development and resistance mechanisms is becoming increasingly understood. Tumor–stroma is the main component of the tumor microenvironment. Stromal cells like cancer-associated fibroblasts (CAFs) are believed to contribute to chemotherapy resistance via the production of several secreted factors like cytokines and chemokines. CAFs are found to influence disease progression; patients with primary tumors with a high amount of tumor–stroma have a significantly worse outcome. Therefore the role of CAFs resistance mechanisms makes them a promising target in anti-cancer therapy. An overview of recent advances in strategies to target breast cancer stroma is given and the current literature regarding these stromal targets is discussed. CAF-specific proteins as well as secreted molecules involved in tumor–stroma interactions provide possibilities for stroma-specific therapy. The development of stroma-specific therapy is still in its infancy and the available literature is limited. Within the scope of personalized treatment, biomarkers based on the tumor–stroma have future potential for the improvement of treatment via image-guided surgery (IGS) and PET scanning.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

scholarly journals Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2795
Author(s):  
Sofia Papanikolaou ◽  
Aikaterini Vourda ◽  
Spyros Syggelos ◽  
Kostis Gyftopoulos
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Therapy Resistance ◽  
Cellular Process ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

scholarly journals Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4800-4812 ◽  
Author(s):  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Ana I. Pozo-Salas ◽  
Antonio J. Martínez-Fuentes ◽  
Luis de Lecea ◽  
...  
Keyword(s):  
Metabolic Phenotype ◽  
Somatostatin Analogue ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ancestral Gene ◽  
Ghrelin Receptor ◽  
Physiological Relevance

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

scholarly journals Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy

2000 ◽  
Vol 57 ◽  
pp. S32-S37 ◽  
Author(s):  
Hendrik Bos ◽  
Steen Andersen ◽  
Peter Rossing ◽  
Dick de Zeeuw ◽  
Hans-Henrik Parving ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapy Resistance ◽  
Patient Factors

scholarly journals Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity

2021 ◽  
Vol 22 (2) ◽  
pp. 540
Author(s):  
Mariam Markouli ◽  
Dimitrios Strepkos ◽  
Kostas A. Papavassiliou ◽  
Athanasios G. Papavassiliou ◽  
Christina Piperi
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Integration Site ◽  
Survival Rates ◽  
Family Members ◽  
Therapy Resistance ◽  
Cellular Functions ◽  
Cns Neoplasms ◽  
Development Regulation

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

scholarly journals The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 439 ◽  
Author(s):  
Vanessa Delcroix ◽  
Olivier Mauduit ◽  
Nolwenn Tessier ◽  
Anaïs Montillaud ◽  
Tom Lesluyes ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Therapy Resistance ◽  
High Grade ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Well Differentiated

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS.

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

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