Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human ...tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN.
Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key ...factor shifting tumors between growth and metastasis.
We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis.
Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT.
Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.
Admission to an intensive care unit (ICU) is associated with increased medical imaging and radiation exposure, yet few studies have estimated the risk of cancer associated with these examinations. ...The purpose of this study was to review computed tomography (CT) scans performed on patients admitted to two urban academic ICUs, predict their radiation exposure, and calculate their estimated lifetime attributable risk of cancer (LAR). An electronic chart review was performed on all CT scans performed between January 2007 and December 2011. The estimated effective dose of radiation was calculated for each CT, and the LAR for each patient was predicted. Mean radiation exposure was 22.2 ± 25.0 mSv with a mean LAR of 0.1 ± 0.2 % and a median of 0.6 % with a range of <0.001 to 3.4 %. Our cohort received radiation doses higher than recommended by guidelines; however, the critical nature of their admission may have warranted these imaging studies. Estimated risk of cancer in this population was overall low.
The salivary gland section in the 4th edition of the World Health Organization classification of head and neck tumors features the description and inclusion of several entities, the most significant ...of which is represented by (mammary analogue) secretory carcinoma. This entity was extracted mainly from acinic cell carcinoma based on recapitulation of breast secretory carcinoma and a shared
ETV6-NTRK3
gene fusion. Also new is the subsection of “Other epithelial lesions,” for which key entities include sclerosing polycystic adenosis and intercalated duct hyperplasia. Many entities have been compressed into their broader categories given clinical and morphologic similarities, or transitioned to a different grouping as was the case with low-grade cribriform cystadenocarcinoma reclassified as intraductal carcinoma (with the applied qualifier of low-grade). Specific grade has been removed from the names of the salivary gland entities such as polymorphous adenocarcinoma, providing pathologists flexibility in assigning grade and allowing for recognition of a broader spectrum within an entity. Cribriform adenocarcinoma of (minor) salivary gland origin continues to be divisive in terms of whether it should be recognized as a distinct category. This chapter also features new key concepts such as high-grade transformation. The new paradigm of translocations and gene fusions being common in salivary gland tumors is featured heavily in this chapter.
Context.—
Salivary gland tumors are rare tumor types for which the molecular understanding has resulted in a rapid expansion and shuffling of entities. These changes are reflected in the 5th edition ...World Health Organization Classification of Head and Neck Tumours (WHO 5th edition), although many nuances still remain.
Objective.—
To review how molecular alterations have helped recategorize, justify, and reinstate entities into our lexicon as well as defining interrelationships between categories, new entities, and subtypes. Furthermore, newer theranostic applications to molecular phenotype will be summarized.
Data Sources.—
World Health Organization Classification of Head and Neck Tumours (WHO 3rd through 5th editions), literature review, personal and institutional experience.
Conclusions.—
Molecular alterations have helped reclassify, retain, and create new categories by augmenting rather than replacing standard criteria. Key entities that have emerged include sclerosing polycystic adenoma, microsecretory adenocarcinoma, and mucinous adenocarcinoma. Molecular phenotypes solidify the range of morphology in established entities such as mucoepidermoid carcinoma and facilitate connectivity between entities. Molecular characteristics now allow for targeted therapeutic approaches for secretory carcinoma and adenoid cystic carcinoma.
Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly ...impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
Basaloid tumors are a common diagnostic problem in salivary gland pathology. However, delineating each of these tumor types is facilitated by an algorithmic approach incorporated by tumor border and ...cell types. This approach greatly diminishes the challenge of separating polymorphous low-grade adenocarcinoma (PLGA) from adenoid cystic carcinoma (ACC). Despite the overlap in growth pattern, ACC is biphasic while PLGA is not. More relevant challenges, namely differentiation of the biphasic basaloid neoplasms including: epithelial-myoepithelial carcinoma (EMCA), cellular pleomorphic adenoma (PA), basal cell adenoma (BCA), and basal cell adenocarcinoma (BCAC), are resolved by a combination of morphologic, immunophenotypic, and to a limited extent, molecular features. Among the most challenging scenarios is high-grade transformation of any of the aforementioned entities. Here, the diagnosis requires recognition of a conventional component and exclusion of metastatic (or in some cases primary) SCC and even select neuroendocrine carcinomas and sarcomas in some cases.
High-Grade Transformation and Carcinosarcoma Verma, Anuj; Seethala, Raja R; Wang, He
Archives of pathology & laboratory medicine,
2024-Apr-04, 2024-04-4, 20240404
Journal Article
Recenzirano
Odprti dostop
High-grade transformation, previously known as dedifferentiation, in salivary gland carcinoma and carcinosarcoma ex pleomorphic adenoma is a rare phenomenon. It is, however, clinically relevant and ...affects treatment and prognosis.
To review the existing literature, describe the histologic and immunophenotypic features, and highlight the diagnostic criteria of high-grade transformation in various salivary gland carcinomas and carcinosarcoma; to review its effect on clinical presentation and prognosis; and to review relevant molecular characteristics and recent concepts and advances.
Literature search in PubMed using key words such as "high-grade transformation," "dedifferentiation," and "carcinosarcoma" in salivary gland. Relevant articles were reviewed, and additional articles were curated from the references of these articles.
High-grade transformation occurs rarely but has a significant impact on prognosis and management. By microscopy, the high-grade area is usually a distinct nodule and shows solid and nested architecture, cellular atypia, high mitotic count, and necrosis. The molecular features are not well established. Carcinosarcoma almost always arises in a pleomorphic adenoma and likely follows an adenoma-carcinoma-sarcoma pathway.
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