ABSTRACT
Most gastrointestinal stromal tumors (GISTs) contain KIT or PDGFRA kinase gain-of-function mutations, and therefore respond clinically to imatinib and other tyrosine kinase inhibitor (TKI) therapies. However, clinical progression subsequently results from selection of TKI-resistant clones, typically containing secondary mutations in the KIT kinase domain, which can be heterogeneous between and within GIST metastases in a given patient. TKI-resistant KIT oncoproteins require HSP90 chaperoning and are potently inactivated by HSP90 inhibitors, but clinical applications in GIST patients are constrained by the toxicity resulting from concomitant inactivation of various other HSP90 client proteins, beyond KIT and PDGFRA. To identify novel targets responsible for KIT oncoprotein function, we performed parallel genome-scale short hairpin RNA (shRNA)-mediated gene knockdowns in KIT-mutant GIST-T1 and GIST882. GIST cells were infected with a lentiviral shRNA pooled library targeting 11 194 human genes, and allowed to proliferate for 5-7 weeks, at which point assessment of relative hairpin abundance identified the HSP90 cofactor, CDC37, as one of the top six GIST-specific essential genes. Validations in treatment-naive (GIST-T1, GIST882) vs imatinib-resistant GISTs (GIST48, GIST430) demonstrated that: (1) CDC37 interacts with oncogenic KIT; (2) CDC37 regulates expression and activation of KIT and downstream signaling intermediates in GIST; and (3) unlike direct HSP90 inhibition, CDC37 knockdown accomplishes prolonged KIT inhibition (>20 days) in GIST. These studies highlight CDC37 as a key biologic vulnerability in both imatinib-sensitive and imatinib-resistant GIST. CDC37 targeting is expected to be selective for KIT/PDGFRA and a subset of other HSP90 clients, and thereby represents a promising strategy for inactivating the myriad KIT/PDGFRA oncoproteins in TKI-resistant GIST patients.
Subject(s)
Cell Cycle Proteins/metabolism , Chaperonins/metabolism , Gastrointestinal Stromal Tumors/metabolism , Gene Expression Regulation, Neoplastic , HSP90 Heat-Shock Proteins/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Survival , Drug Resistance, Neoplasm , Gene Expression Profiling , Gene Library , Humans , Lentivirus/metabolism , Oncogenes , Pentacyclic Triterpenes , Protein Kinase Inhibitors/chemistry , RNA, Small Interfering/metabolism , Triterpenes/chemistryABSTRACT
Amyloid is a proteinaceous material that is deposited in the tissues in a large variety of clinical contexts; in the skin it can be found with or without concomitant systemic disease. Primary localized cutaneous amyloidosis encompasses those amyloidoses restricted to the skin without involvement of other systems. The most common forms within this group are macular and lichen amyloidosis. Nodular amyloidosis is extremely rare, and there are notable differences in clinical presentation, prognosis, histology, and pathogenesis between this entity and the macular and lichenoid variants. We report a new case of nodular primary localized cutaneous amyloidosis with disseminated plaques and nodules in which no systemic disease developed in the 3 years following the appearance of the lesions.
Subject(s)
Amyloidosis/pathology , Skin Diseases/pathology , Adult , Female , HumansABSTRACT
El amiloide es un material proteináceo que se deposita en los tejidos en una gran variedad de situaciones clínicas; en la piel puede ser hallado con o sin afectación sistémica concomitante. La amiloidosis cutánea primaria localizada designa a aquellas amiloidosis con afectación exclusivamente cutánea, sin afectación a otros niveles. Las formas más comunes dentro de este grupo son la amiloidosis macular y el liquen amiloideo. La amiloidosis nodular es extremadamente infrecuente y mantiene importantes diferencias clínicas, pronósticas, histológicas y patogénicas con respecto a las variantes macular y liquenoide. Presentamos un nuevo caso de amiloidosis cutánea primaria localizada nodular con placas y nódulos diseminados, que no desarrolló afectación sistémica tras tres años desde el debut de las lesiones (AU)
Amyloid is a proteinaceous material that is deposited in the tissues in a large variety of clinical contexts; in the skin it can be found with or without concomitant systemic disease. Primary localized cutaneous amyloidosis encompasses those amyloidoses restricted to the skin without involvement of other systems. The most common forms within this group are macular and lichen amyloidosis. Nodular amyloidosis is extremely rare, and there are notable differences in clinical presentation, prognosis, histology, and pathogenesis between this entity and the macular and lichenoid variants. We report a new case of nodular primary localized cutaneous amyloidosis with disseminated plaques and nodules in which no systemic disease developed in the 3 years following the appearance of the lesions (AU)
Subject(s)
Humans , Adult , Female , Amyloidosis/complications , Amyloidosis/diagnosis , Amyloidosis/therapy , Immunohistochemistry/methods , Radiography, Thoracic/methods , Radiography, Thoracic/trends , Cryotherapy , Electrocoagulation , Amyloidosis/pathology , Skin Diseases/pathology , Amyloidosis/classification , Amyloidosis/physiopathology , Immunohistochemistry/trends , Bone Marrow/surgeryABSTRACT
La información proporcionada por la biopsia testicular en los estados intersexuales es primordial para la identificación, clasificación y detección precoz de neoplasias en estos pacientes. Antes de decidir una determinada opción terapéutica, los datos del estudio histológico de la biopsia gonadal deberán ser evaluados junto con los datos clínicos, genéticos, hormonales y moleculares. La diferenciación sexual es el resultado de complejos mecanismos genéticos y endocrinos, por ello, en el presente trabajo se revisan en primer lugar los acontecimientos que ocurren en el desarrollo embrionario de las gónadas, atendiendo a los mecanismos genéticos implicados en la determinación sexual y en la diferenciación testicular y del tracto urogenital. En segundo lugar se revisan los distintos tipos de gónadas observadas en los desórdenes del desarrollo sexual (síndromes de regresión testicular, cintilla fibrosa, disgenesia testicular, cintilla testículo, ovotestes, testículos microscópicamente normales y ovario), haciendo énfasis en los datos histológicos presentes en cada uno de ellos y en los datos diferenciales que permiten al patólogo distinguir unos desórdenes de otros, junto con la integración de los datos clínicos, genéticos hormonales y moleculares de cada una de estas situaciones. En tercer lugar se considera la incidencia de neoplasias, tanto en las diferentes situaciones clásicamente llamadas disgenesia gonadal, como de pseudohermafroditismos masculinos y hermafroditismo verdadero. Por último, se comentan las limitaciones de la biopsia gonadal que pueden impedir que el patólogo llegue a un diagnóstico preciso de un desórden del desarrollo sexual
The gonadal biopsy provides essential information for the identification, classification and early detection of neoplasias in patients with disorders of sex development. Histopathological findings in these cases must be analysed together with clinical, hormonal, genetic and molecular information before deciding a therapeutic option. Sexual differentiation is the result of multiple and complex genetic and endocrinal mechanisms; therefore, we first present the events taking place during gonadal embryonic development, focusing on the genetic mechanisms involved in sexual determination and the differentiation of the testis and the urogenital tract. In second place, we describe the different gonads in the intersexual states -in testicular regression syndrome, fibrous streak, testicular dysgenesis, streak testes, ovotestes and microscopically normal testes and ovaries-, highlighting the histological features and the differential findings that allow the pathologist to distinguish between these entities with the aid of clinical, genetic, hormonal and molecular information that are characteristic for each situation. In third place, we studied the incidence of neoplasias in gonadal dysgenesis, male pseudohermaphroditism and true hermaphroditism. Finally, we discuss the limitations of gonadal biopsy to achieve a correct diagnosis in the disorders of sex development
Subject(s)
Male , Humans , Biopsy/methods , Gonadal Disorders/diagnosis , Sex Differentiation/genetics , Sex Differentiation/physiology , Disorders of Sex Development/diagnosis , Disorders of Sex Development/diagnosis , Disorders of Sex Development/surgery , Sertoli Cell Tumor/diagnosis , Testicular Neoplasms/classification , Testicular Neoplasms/diagnosis , Sertoli Cells/cytology , Gonadal Disorders/surgery , Embryonic and Fetal Development/genetics , Embryonic and Fetal Development/physiology , Neoplasms, Gonadal Tissue/diagnosis , Neoplasms, Gonadal Tissue/surgerySubject(s)
Cytoplasmic Granules/pathology , Dilatation, Pathologic/pathology , Epididymis/pathology , Epithelial Cells/pathology , Lysosomes/pathology , Adolescent , Adult , Aged , Biomarkers/metabolism , Cytoplasmic Granules/metabolism , Dilatation, Pathologic/complications , Dilatation, Pathologic/metabolism , Epididymis/metabolism , Epithelial Cells/metabolism , Humans , Lysosomes/metabolism , Male , Metaplasia/complications , Metaplasia/metabolism , Metaplasia/pathology , Paneth Cells/metabolism , Paneth Cells/pathology , Seminoma/complications , Seminoma/pathology , Seminoma/surgery , Testicular Neoplasms/complications , Testicular Neoplasms/pathology , Testicular Neoplasms/surgeryABSTRACT
The gonadal biopsy provides essential information for the identification, classification and early detection of neoplasias in patients with disorders of sex development. Histopathological findings in these cases must be analysed together with clinical, hormonal, genetic and molecular information before deciding a therapeutic option. Sexual differentiation is the result of multiple and complex genetic and endocrinal mechanisms; therefore, we first present the events taking place during gonadal embryonic development, focusing on the genetic mechanisms involved in sexual determination and the differentiation of the testis and the urogenital tract. In second place, we describe the different gonads in the intersexual states -in testicular regression syndrome, fibrous streak, testicular dysgenesis, streak testes, ovotestes and microscopically normal testes and ovaries-, highlighting the histological features and the differential findings that allow the pathologist to distinguish between these entities with the aid of clinical, genetic, hormonal and molecular information that are characteristic for each situation. In third place, we studied the incidence of neoplasias in gonadal dysgenesis, male pseudohermaphroditism and true hermaphroditism. Finally, we discuss the limitations of gonadal biopsy to achieve a correct diagnosis in the disorders of sex development.