Scott S. Strugnell

Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors.

Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine-phosphorylated caveolin-1

Both tyrosine-phosphorylated caveolin-1 (pY14Cav1) and GlcNAc-transferase V (Mgat5) are linked with focal adhesions (FAs); however, their function in this context is unknown. Here, we show that galectin-3 binding to Mgat5-modified N-glycans functions together with pY14Cav1 to stabilize focal adhesion kinase (FAK) within FAs, and thereby promotes FA disassembly and turnover. Expression of the Mgat5/galectin lattice alone induces FAs and cell spreading. However, FAK stabilization in FAs also requires expression of pY14Cav1. In cells lacking the Mgat5/galectin lattice, pY14Cav1 is not sufficient to promote FAK stabilization, FA disassembly, and turnover. In human MDA-435 cancer cells, Cav1 expression, but not mutant Y14FCav1, stabilizes FAK exchange and stimulates de novo FA formation in protrusive cellular regions. Thus, transmembrane crosstalk between the galectin lattice and pY14Cav1 promotes FA turnover by stabilizing FAK within FAs defining previously unknown, interdependent roles for galectin-3 and pY14Cav1 in tumor cell migration.

Diagnostic utility of galectin-3 in thyroid cancer.

Galectin-3 (Gal-3), which has received significant recent attention for its utility as a diagnostic marker for thyroid cancer, represents the most well-studied molecular candidate for thyroid cancer diagnosis. Gal-3 is a protein that binds to beta-galactosidase residues on cell surface glycoproteins and has also been identified in the cytoplasmic and nuclear compartment. This marker has been implicated in regulation of normal cellular proliferation and apoptosis, as well as malignant transformation and the metastasis of cancer cells. We here present a mechanistic review of Gal-3 and its role in cancer development and progression. Gal-3 expression studies in thyroid tissue and cytologic tumor specimens and their methodological considerations are also discussed in this article. Despite great variance in their methodology, the majority of immunohistochemical studies found that Gal-3 was differentially expressed in thyroid carcinoma compared with benign and normal thyroid specimens, suggesting that Gal-3 is a good diagnostic marker for thyroid cancer. Recent studies have also demonstrated improved methodological reliability. On the other hand, Gal-3 genomic expression studies have shown inconsistent results for diagnostic utility and are not recommended. Overall, the development of Gal-3 as a diagnostic marker for thyroid cancer represents a promising avenue for future study, and its clinical application could significantly reduce the number of diagnostic thyroid operations performed for cases of indeterminant fine needle aspiration biopsy cytology, and thus positively impact the current management of thyroid nodular disease.

Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation

Phosphocaveolin-1 regulates a positive feedback loop that responds to mechanical stress to induce caveola biogenesis by relieving Egr1 transcriptional inhibition of caveolin-1 and cavin-1.

Anaplastic thyroid cancer: a comprehensive review of novel therapy

Thyroid carcinomas are the most common cancer of the human endocrine system and are typically classified as papillary, follicular, anaplastic or medullary carcinomas. Although epidemiological studies have suggested an increased incidence of anaplastic thyroid carcinomas (ATCs) worldwide, there has been little evidence to suggest that, with current treatment, there has been any improvement in patient survival over the past two decades. Anaplastic thyroid carcinoma is one of the most aggressive human malignancies and is responsible for a disproportionate number of thyroid cancer-related deaths. Currently, available therapy for ATCs includes: chemotherapy, radiotherapy and surgery. Due to the poor treatment outcomes for individuals diagnosed with ATCs who undergo conventional therapy, novel therapeutic strategies for the treatment of ATCs are urgently needed. In this article, we review the existing management of ATCs, with a focus on novel molecular-targeted approaches as described in preclinical studies and in early human clinical trials.

Coordinated expression of galectin-3 and caveolin-1 in thyroid cancer†

Galectin‐3 (Gal3) is the single most accurate marker for the diagnosis of differentiated thyroid cancer (DTC). Gal3 overrides the tumour suppressor activity of caveolin‐1 (Cav1) and functions in concert with Cav1 to promote focal adhesion turnover and tumour cell migration and invasion. To study their coordinated role in progression of a human cancer, we investigated the expression of Gal3 and Cav1 in specimens of human benign thyroid lesions, DTC and anaplastic thyroid cancer (ATC). Gal3 and Cav1 expression is significantly associated with DTC and ATC, but not benign nodules. Essentially all Cav1‐positive DTC cancers express Gal3, supporting the synergistic activity of these two proteins in DTC progression. Similarly, coordinated elevated Gal3/Cav1 expression was observed in three DTC‐derived cell lines (papillary TCP1 and KTC1 and follicular FTC133) but only one (ACT1) of five ATC‐derived cell lines. Using siRNA knockdown, Gal3 and Cav1 were shown to be required for RhoA GTPase activation, stabilization of focal adhesion kinase (FAK; a measure of focal adhesion signalling and turnover) and increased migration of the DTC cell lines studied, but not the ATC cell lines, including ACT1, which expresses elevated levels of Gal3 and Cav1. Co‐expression of Gal3 and Cav1 in the T238 anaplastic cell line stabilized FAK‐GFP in focal adhesions. Gal3 and Cav1 therefore function synergistically to promote focal adhesion signalling, migration and progression of DTC. Copyright

Hemithyroidectomy is the preferred initial operative approach for an indeterminate fine needle aspiration biopsy diagnosis

BACKGROUND Fine needle aspiration biopsy represents the critical initial diagnostic test used for evaluation of thyroid nodules. Our objectives were to determine the cytological distribution, the utility of clinicopathologic characteristics for predicting malignancy and the true proportion of cancer among individuals who presented with indeterminate cytology and had undergone thyroid surgery for suspicion of cancer. METHODS We retrospectively reviewed 1040 consecutive primary thyroid operations carried out over an 8-year period at a tertiary care endocrine referral centre. Follicular neoplasm (FN), Hürthle cell neoplasm (HN), neoplasms suspicious for but not diagnostic of papillary carcinoma (IP) and neoplasms with cellular atypia (IA) were reviewed. RESULTS In all, 380 individuals presented with cytologically indeterminate thyroid nodules. Of these, 252 (66%) patients had FN, 47 (12%) HN, 44 (12%) IP, 26 (7%) IA and 11 (4%) had mixed diagnoses. Biopsied lesions were found to be malignant on pathological evaluation in 102 (27%) patients: 49 (19%) with FN, 11 (23%) HN, 28 (64%) IP and 9 (35%) with IA. Hemithyroidectomy was adequate definitive treatment in 196 of 225 (87%) patients with FN and 39 of 42 (93%) with HN. Significant associations with a cancer diagnosis were identified for smaller tumour size in patients with FN (p = 0.004) and right thyroid lobe location in patients with IP (p = 0.012), although these factors were nonsignificant in the corrected analyses for multiple comparisons. CONCLUSION In a review of the experience at a Canadian centre, 4 operations were carried out to identify each cancer, and hemithyroidectomy was the optimal initial and definitive surgical approach for most patients.

Gender differences in thyroid cancer: a critical review

It has long been known that the incidence of thyroid cancer in women is significantly higher than that in men. The objective of this article is to review gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy. Although more common in women, thyroid cancer typically presents at a more advanced stage and with a worse disease prognosis in men. Clinical evidence on the impact of estrogen and other sex hormones on thyroid cancer has remained inconclusive, although numerous experimental studies have suggested that these hormones and their receptors may play a role in tumorigenesis and tumor progression. Studies of thyroid cancer cell lines suggest that an imbalance between the two estrogen receptor (ER) isoforms, α and β, may be responsible for the cell proliferation seen with estrogen treatment. Expression studies on thyroid tumors indicate that they express ER and possibly progesterone receptors and androgen receptors, but there is conflicting evidence as to whether or not there is a difference in receptor status between thyroid cancers, benign thyroid lesions and normal thyroid tissue. There have been few studies evaluating the ERα/ERβ profiles in thyroid tumors and normal thyroid tissue. Our understanding of the underlying basis for sex differences in thyroid cancer has improved over the last few decades, but the relationship between gender and thyroid cancer risk has remained elusive. Areas for future research include ERα/ERβ profiling of normal and neoplastic thyroid tissue, association between ER status and tumor dedifferentiation, and evaluation of the signaling pathways by which estrogen and other sex steroids exert their effects on thyroid cancer cells. Sex steroid receptors, and then downstream signaling pathways, represent promising future therapeutic targets for thyroid cancer treatment, and further study is required.

Synoptic pathology reporting for thyroid cancer: a review and institutional experience

Thyroid cancer surgical pathology reports contain information that is critical for diagnosis, determining completeness of resection, staging and guiding postoperative management. Traditional narrative pathology reporting is prone to errors and omissions with variability in content and completeness. The objective of this review was to evaluate the impact of synoptic reporting on thyroid cancer pathology reporting. Our institutional study of pathology reporting of differentiated thyroid cancers at a Canadian tertiary care institution relative to the College of American Pathologists checklists is also presented and critically evaluates deficiencies in the narrative pathology reporting format.