scholarly journals Regulators of the RAS-ERK pathway as therapeutic targets in thyroid cancer

2019 ◽  
Vol 26 (6) ◽  
pp. R319-R344 ◽  
Author(s):  
Miguel A Zaballos ◽  
Adrián Acuña-Ruiz ◽  
Marta Morante ◽  
Piero Crespo ◽  
Pilar Santisteban
Keyword(s):  
Thyroid Cancer ◽  
Human Cancer ◽  
Clinical Success ◽  
Therapeutic Targets ◽  
Relevant Information ◽  
Erk Pathway ◽  
Tumor Resistance ◽  
Thyroid Carcinomas ◽  
Complex Signaling ◽  
Spatial Specificity

Thyroid cancer is mostly an ERK-driven carcinoma, as up to 70% of thyroid carcinomas are caused by mutations that activate the RAS/ERK mitogenic signaling pathway. The incidence of thyroid cancer has been steadily increasing for the last four decades; yet, there is still no effective treatment for advanced thyroid carcinomas. Current research efforts are focused on impairing ERK signaling with small-molecule inhibitors, mainly at the level of BRAF and MEK. However, despite initial promising results in animal models, the clinical success of these inhibitors has been limited by the emergence of tumor resistance and relapse. The RAS/ERK pathway is an extremely complex signaling cascade with multiple points of control, offering many potential therapeutic targets: from the modulatory proteins regulating the activation state of RAS proteins to the scaffolding proteins of the pathway that provide spatial specificity to the signals, and finally, the negative feedbacks and phosphatases responsible for inactivating the pathway. The aim of this review is to give an overview of the biology of RAS/ERK regulators in human cancer highlighting relevant information on thyroid cancer and future areas of research.

scholarly journals Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment

2019 ◽  
Vol 20 (13) ◽  
pp. 3258 ◽  
Author(s):  
Livia Manzella ◽  
Michele Massimino ◽  
Stefania Stella ◽  
Elena Tirrò ◽  
Maria Stella Pennisi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Thyroid Neoplasms ◽  
Thyroid Carcinomas ◽  
Signaling Inhibitors ◽  
Poorly Differentiated ◽  
Biological Entities ◽  
Complex Signaling ◽  
Igf Signaling

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)—comprising papillary (PTC) and follicular (FTC) tumors—respond to radioiodine therapy, while undifferentiated tumors—including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)—are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

scholarly journals Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 739
Author(s):  
Taeju Park
Keyword(s):  
Tumor Cell ◽  
Cancer Treatment ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Therapeutic Targets ◽  
Viral Oncoprotein ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs ◽  
Cell Functions

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

Clonally Related But Phenotypically Divergent Human Cancer Cell Lines Derived from a Single Follicular Thyroid Cancer Recurrence (TT2609)

Thyroid ◽  
2001 ◽  
Vol 11 (10) ◽  
pp. 909-917 ◽  
Author(s):  
Albert A. Geldof ◽  
Richard T. Versteegh ◽  
Johan C. van Mourik ◽  
Martin A. Rooimans ◽  
Fre Arwert ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Recurrence ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Follicular Thyroid Cancer ◽  
Human Cancer Cell Lines ◽  
Thyroid Cancer Recurrence

Photocontrolling Microtubule Dynamics with Photoswitchable Chemical Reagents

2021 ◽  
Author(s):  
Oliver Thorn-Seshold ◽  
Joyce Meiring
Keyword(s):  
3D Culture ◽  
3D Cell Culture ◽  
Relevant Information ◽  
Microtubule Dynamics ◽  
Model Organisms ◽  
Chemical Reagents ◽  
Cellular Assays ◽  
General Protein ◽  
Spatial Specificity

Microtubule dynamics can be inhibited with sub-second temporal resolution and cellular-scale spatial resolution, by using precise illuminations to optically pattern where and when photoswitchable microtubule-inhibiting chemical reagents exert their latent bioactivity. The recently-available reagents (SBTub, PST, STEpo, AzTax, PHTub) now enable researchers to use light to reversibly modulate microtubule-dependent processes in eukaryotes, in 2D and 3D cell culture as well as in vivo, across a variety of model organisms: with applications in fields from cargo transport to cell migration, cell division, and embryonic development.<br><br>However, a wide knowledge gap has remained in the literature, which has blocked further translation of these and many other classes of photopharmaceuticals. No generally-applicable procedures or workflows to establish biological assays using photopharmaceuticals have been published. Accordingly, the rate of adoption of photopharmaceutical tools in the broader chemical biology community (beyond the original chemical developers of the tools) has remained very low. Vital information about assay benchmarking for photoconversion, testing for isomer solubility, proving the retention of mechanism of action, estimating the limits of phototoxicity etc has either simply not been formalised in the literature, or has remained buried in diverse reports without being unified and codified for an audience beyond that of synthetic organic chemists.<br><br>Here we have developed a robust four-step assay establishment procedure to optimise assay parameters for achieving reliable photocontrol over microtubule dynamics, that is applicable to diverse families of photoswitchable inhibitors. This procedure also controls for these common sources of irreproducibility and includes numerous troubleshooting steps. We also collect together the relevant information for non-chemist "users" such as microscopists and biologists, to introduce the theory of small molecule photoswitching; the unique features, usage requirements, and limitations that photoswitchable chemical reagents have; and the specific performance features of the major classes of photoswitchable microtubule inhibitors that are currently available; to highlight their properties that suit them to different applications. The generally-applicable workflows that we present allow establishing cellular assays optically controlling microtubule dynamics in a temporally reversible fashion with spatial specificity down to a single selected cell within a field of view. These workflows and methods also equip the reader to tackle advanced uses of photoswitchable chemical reagents for general protein targets, in 3D culture and in vivo, and can represent an important bridge to reach the high-value biological applications that photopharmacology can promise.<br>

scholarly journals Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1382 ◽  
Author(s):  
Mohamed Aashiq ◽  
Deborah A. Silverman ◽  
Shorook Na’ara ◽  
Hideaki Takahashi ◽  
Moran Amit
Keyword(s):  
Thyroid Cancer ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Sodium Iodide Symporter ◽  
Tumor Resistance ◽  
Loss Of Function ◽  
Iodide Uptake ◽  
Mitogen Activated Protein ◽  
Recurrent Thyroid Cancer

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

scholarly journals Evaluation of Gene Expression Profiles in Thyroid Nodule Biopsy Material to Diagnose Thyroid Cancer

2008 ◽  
Vol 93 (4) ◽  
pp. 1195-1202 ◽  
Author(s):  
Stéphanie Durand ◽  
Carole Ferraro-Peyret ◽  
Samia Selmi-Ruby ◽  
Christian Paulin ◽  
Michelle El Atifi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Cancer ◽  
Normal Tissue ◽  
Large Scale ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Correct Diagnosis ◽  
Thyroid Tissue ◽  
Biopsy Material ◽  
Thyroid Carcinomas

Abstract Context: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. Objective: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. Design: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. Results: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. Conclusions: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study.

scholarly journals Thyroid Cancer Cell Resistance to gefitinib Depends on the Constitutive Oncogenic Activation of the ERK Pathway

2013 ◽  
Vol 98 (6) ◽  
pp. 2502-2512 ◽  
Author(s):  
Francesco Frasca ◽  
Veronica Vella ◽  
Maria Luisa Nicolosi ◽  
Rosa Linda Messina ◽  
Fiorenza Gianì ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Thyroid Cancer Cell ◽  
Epidermal Growth ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Context: Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas. Objective: We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors. Design: We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines. Results: We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRASG12A/Q61R mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors. Conclusions: These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.

scholarly journals Thyroid Carcinoma in Hot Nodules: Review of the Literature

2013 ◽  
Vol 5 (2) ◽  
pp. 50-54 ◽  
Author(s):  
Pouya Iranmanesh ◽  
Marc Pusztaszeri ◽  
John Robert ◽  
Patrick Meyer ◽  
Boris Schiltz ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Clinical Case ◽  
Survival Rates ◽  
Review Of The Literature ◽  
Abnormal Finding ◽  
Thyroid Cancers ◽  
Thyroid Carcinomas ◽  
Medical Databases ◽  
The Past

ABSTRACT Thyroid hot nodules are virtually always considered benign. Rare cases of hot thyroid carcinoma exist. We briefly described a clinical case and performed a review of the literature. We performed an extensive research on medical databases, such as PubMed and compiled all published cases matching preset criteria defining true hot thyroid carcinomas as well as guidelines regarding their management. We analyzed 103 articles published over the past 50 years. We selected 16 articles, including 45 cases matching our criteria. The majority were follicular carcinomas. Papillary carcinomas were infrequently found in this setting. Recommended management and survival rates were similar to classical cold thyroid cancer. Although hot nodules should continue to be considered benign most of the time, rare cases of hot thyroid cancers exist and clinicians should not hesitate to ask for additional tests if they encounter any abnormal finding. This form of thyroid cancer can reasonably be managed the same way as the cold thyroid cancers. How to cite this article Iranmanesh P, Pusztaszeri M, Robert J, Meyer P, Schiltz B, Sadowski SM, Goumaz MO, Triponez F. Thyroid Carcinoma in Hot Nodules: Review of the Literature. World J Endoc Surg 2013;5(2):50-54.

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