Primary cilia in gastrointestinal stromal tumors (original) (raw)
Related papers
Primary cilia in gastric Gastrointestinal Stromal Tumours (GISTs): an ultrastructural study
Journal of Cellular and Molecular Medicine, 2013
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal (non-epithelial) neoplasms of the human gastrointestinal (GI) tract. They are thought to derive from interstitial cells of Cajal (ICCs) or an ICC progenitor based on immunophenotypical and ultrastructural similarities. Because ICCs show primary cilium, our hypothesis is based on the possibility that some of these neoplastic cells could also present it. To determine this, an exhaustive ultrastructural study has been developed on four gastric GISTs. Previous studies had demonstrated considerable variability in tumour cells with two dominating phenotypes, spindly and epithelioid. In addition to these two types, we have found another cell type reminiscent of adult ICCs with a voluminous nucleus surrounded by narrow perinuclear cytoplasm with long slender cytoplasmic processes. We have also noted the presence of small undifferentiated cells. In this study, we report for the first time the presence of primary cilia (PCs) in spindle and epithelioid tumour cells, an ultrastructural feature we consider of special interest that has hitherto been ignored in the literature dealing with the ultrastructure of GISTs. We also point out the frequent occurrence of multivesicular bodies (MVBs). The ultrastructural findings described in gastric GISTs in this study appear to be relevant considering the critical roles played by PCs and MVBs recently demonstrated in tumourigenic processes.
Annals of Oncology, 2016
The primary cilium is a solitary, sensory, immotile microtubule-based structure that arises from the centrosome and is projected from the surface of most human cell types. It has been hypothesized that primary cilia could serve as a tumor suppressor organelle. The objective of this pilot study was to investigate the presence and frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma and to evaluate the prognostic significance of their frequency. Methods: The presence of primary cilia in cells in samples of small bowel (8 patients) and colorectal adenocarcinoma (32 patiens) was evaluated. The primary cilia of cells were immunofluorescently labeled using primary monoclonal anti-acetylated α-tubulin antibody and cell nuclei were labeled using DAPI. Results: Primary cilia were identified in all examined specimens. The median frequency of primary cilia was 0.49% in cells of small bowel cancer and 0.22% in cells in colorectal cancer. Overall survival according to frequency of primary cilia in all intestinal adenocarcinomas was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) in univariate analysis (p=0.007) and also in the Cox proportional hazard model (p=0.032). Overall survival according to frequency of primary cilia in colorectal adenocarcinoma was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) (p=0.028). Conclusions: The present pilot study provides the first evidence of the prognostic significance of the frequency of primary cilia in small bowel and colorectal adenocarcinoma. Because of significantly higher median frequency of primary cilia in the rare small bowel adenocarcinoma than in the frequent colorectal adenocarcinoma (p<0.001), the results of this study support a potential role for primary cilia as a biomarker in these types of cancer.
Archive of oncology, 2002
Gastrointestinal stromal tumors (GISTs) represent a distinct and the most important subset of mesenchymal tumors of the gastrointestinal (GI) tract GISTs occur throughout the GI tract but are usually located in the stomach and small intestine. The cellular origin, differentiation, nomenclature and prognosis of GISTs are controversial. Because GISTs, like the interstitial cells of Cajal, the GI pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the Cajal cells has recently been suggested. GISTs are also known for their wide variability in clinical behavior and for the difficulty to determine their malignant condition The most reproducible predictors of malignancy are mitotic count >1-5 per10 high-powered fields (HPF), size >5 cm, tumor necrosis, infiltration and metastasis to other sites. However, some tumors with mitotic activity <1/10 HPF may metastasize indicating some uncertainty in malignant potential of GISTs, especially those larger than 5 cm. Re...
Cilia are microtubule-based organelles, which are ubiquitously expressed in epithelial cells. Cholangiocytes, the epithelial cells lining the biliary tree, have primary cilia extending from their apical plasma membrane into the ductal lumen, where the cilia function as multisensory organelles transducing environmental cues into the cell interior. The decrease or loss of primary cilia has been described in several malignancies, including cholangiocarcinoma, suggesting that the loss of cilia is a common occurrence in neoplastic transformation. In this short review, we describe the expression of cilia in several cancers, explore the mechanisms and consequences of ciliary loss, and discuss the potential use of the primary cilia as therapeutic targets.
Gastrointestinal Stromal Tumors: An Ultrastructural Study
International Journal of Surgical Pathology, 2002
Gastrointestinal stromal tumors (GISTs) represent an enigmatic group of lesions of uncertain phenotype and biologic potential. Although earlier studies suggested smooth muscle cells, schwann cells, or neuronal differentiation, more recent evidence indicates that these tumors show phenotypic features that are similar to the interstitial cells of Cajal. Recently, investigators have begun to evaluate these lesions in a site-specific manner and have found that, in addition to morphologic differences between them, their biologic behavior also appears to be linked to their anatomic location. Many of these studies have emphasized the histologic and immunophenotypic features of GISTs in relation to their sites of origin, however, their site-specific ultrastructural characteristics have received little attention in the literature. In this study, we evaluated 34 GISTs (15 gastric, 12 small intestinal, 4 colonic, and 3 omental) for a variety of ultrastructural features in an effort to identify site-specific similarities and differences. Tumors predominantly composed of epithelioid cells were more commonly seen in gastric (60%) and omental (67%) tumors than in those of the small intestine (33%) and colon (0%). Cytoplasmic filaments and intercellular junctions were commonly seen in tumors from all locations, the filaments frequently forming paranuclear aggregates in the epithelioid cells. Tumors from all sites were composed of cells with surface filopodia and interdigitating cell processes, but in tumors of the stomach and omentum the filopodia were usually short and minimally intertwined, whereas those of small and large intestinal GISTs were characteristically long and complex. Basal lamina, though poorly formed, was present only in tumors of gastric and omental origin (13% and 67%, respectively). Pinocytotic vesicles were also seen in tumors from these sites (33% of gastric tumors and 67% of omental lesions) as well as those of the small intestine (17%) and the colon (25%). None of the gastric or omental tumors had microtubules; they were, however, seen in small intestinal (33%) and colonic (25%) stromal tumors. Skenoid fibers were seen in 33% of small intestinal GISTs and 1 metastatic gastric GIST. Overall, gastric and omental tumors have better developed features of myogenic differentiation and have blunt filopodia and minimally intertwined cell processes. Indeed, these 2 groups are indistinguishable ultrastructurally, raising the possibility that the genesis of omental GISTs is similar to that of gastric stromal tumors. Small intestinal stromal tumors have characteristic interdigitating cell processes and numerous elongate filopodia-like structures harboring intercellular junctions as well as microtubules and extracellular skenoid fibers. The constituent cells in colonic stromal tumors, while more reminiscent of small intestinal stromal, were frequently more primitive in appearance. In conclusion, GISTs from different anatomic locations share many overlapping ultrastructural characteristics; however, a few features are distinctive. It is hoped that these findings will aid in their recognition and contribute to the classification of this heterogeneous group of neoplasms. Int J Surg Pathol 10(2): [101][102][103][104][105][106][107][108][109][110][111][112][113] 2002
Detection of primary cilia in human glioblastoma
Journal of Neuro-Oncology, 2014
Glioblastoma (GBM) is the most common malignant adult brain tumor and carries a poor prognosis due to primary and acquired resistance. While many cellular features of GBM have been documented, it is unclear if cells within these tumors extend a primary cilium, an organelle whose associated signaling pathways may regulate proliferation, migration, and survival of neural precursor and tumor cells. Using immunohistochemical and electron microscopy (EM) techniques, we screened human GBM tumor biopsies and primary cell lines for cilia. Immunocytochemical staining of five primary GBM cell lines revealed that between 8 and 25 % of the cells in each line possessed gamma tubulin-positive basal bodies from which extended acetylated, alpha-tubulinpositive axonemes. EM analyses confirmed the presence of cilia at the cell surface and revealed that their axonemes contained organized networks of microtubules, a structural feature consistent with our detection of IFT88 and Arl13b, two trafficked cilia proteins, along the lengths of the axonemes. Notably, cilia were detected in each of 23 tumor biopsies (22 primary and 1 recurrent) examined. These cilia were distributed across the tumor landscape including regions proximal to the vasculature and within necrotic areas. Moreover, ciliated cells within these tumors co-stained with Ki67, a marker for actively dividing cells, and ZEB1, a transcription factor that is upregulated in GBM and linked to tumor initiation, invasion, and chemoresistance. Collectively, our data show that subpopulations of cells within human GBM tumors are ciliated. In view of mounting evidence supporting roles of primary cilia in tumor initiation and propagation, it is likely that further study of the effects of cilia on GBM tumor cell function will improve our understanding of GBM pathogenesis and may provide new directions for GBM treatment strategies.
2014
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the GI tract. They occur most frequently in stomach (60-70%), or small intestine(SI) (25-30%). Rare sites include colon, rectum, appendix and esophagus (<10%). On histology their appearance varies from cellular spindle cell tumours to epithelioid to pleomorphic tumours. Traditionally, three criteria have been used to determine malignancy, which include site of origin (SI and rectal tumours are more aggressive than stomach tumours), tumour size(>5 cm) and mitotic rate.(>5/50 hpf).GISTs are characterized by gain of function mutation in c kit (CD117) proto oncogene most commonly involving exon 11. GISTs without c kit mutation show mutations in platelet derived growth factor receptor alpha(PDGFRα).Surgery has been the standard treatment for resectable GISTs, but metastatic and unresectable GISTs had a poor prognosis. Recent molecular advances have opened new vistas leading to the development of specific molecular targeted therapies which stabilize the disease and reduce the frequency of disease recurrence. This review summarizes our existing knowledge, recent advances regarding histogenesis, pathology, molecular biology, and targeted cancer therapies which has revolutionized the management of these diseases.
Clinical and Molecular Anatomy of Gastrointestinal Stromal Tumors (GIST)
—Introduction Gastrointestinal stromal tumors GISTs are rare and fall into the category of non-epithelial tumors of the gastrointestinal tract , involving the stomach at a higher percentage (70 %). The purpose of this study , through a retrospective analysis of the observed cases , is to obtain data on the incidence , survival curve identification of prognostic and predictive parameters .The goal is to collect data concerning the natural history of GIST , 65% of patients were female, 35% male , mean age 64 years. Metastatic disease was assessed by cd171. In this study, n 11 (65 %) cases were L1 (cd171) positive for smooth muscle tumors. Of which 8 with headquarters in the stomach, ileum en 3. Investigations have been performed immunohistochemistry with CD117 , CD99 , ema. all enrolled patients tested positive for CD117 .Discussion Thread What are the prognostic factors of GiST is still a matter of debate, but the consensus conference (NIH) in 2001 defined BETHESTHA n 2 parameters which are: the size and mitotic index of 50 HP for the lesions found were reported as accidental the size ranged < 10mm to > 50mm. .. The study carried out shows that the markers are the key to the histological diagnosis of GIST malignancies in GIST have introduced anti-angiogenic therapy with administration of sunitinib at a dose of 50mg/die for 4 weeks every 6. For the purpose of inhibiting tumor growth with a time of disease-free interval longer. It is evident that in the histological diagnosis of GIST are inserted reporting the results of molecular biology with immunohistochemical markers , in combination with mitotic index , and tumor size in order to define a complete risks MTS Index Terms—Intestinal Tumors Histology GIST.
2005
Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: a potential diagnostic pitfall Aims: The diagnosis of gastrointesinal stromal tumours (GISTs) is widely based on morphological features and KIT (CD117) immunoreactivity. Most patients with advanced GISTs show a major clinical response after treatment with imatinib mesylate. The histopathological features of GISTs in patients on prolonged imatinib treatment have, thus far, not been addressed in detail. In this report, we present three patients with metastatic GISTs, who received more than 1 year of therapy with imatinib, and whose tumours changed their morphological and immunohistochemical characteristics during continued treatment with the drug. Methods and results: All three primary GISTs from these patients were classical spindle-type tumours, showing diffuse, strong CD117, CD34, and focal a-smooth muscle actin expression. During treatment, two clinically progressive and one clinically stable GIST revealed a diffuse epithelioid, or pseudopapillary epithelioid growth pattern, characterized by rounded cells with eosinophilic cytoplasm and uniform round-to-ovoid nuclei. In addition, GIST specimens from patients on therapy showed complete loss of CD117 immunoreactivity. Remarkably, two of these tumours also became CD34 immunonegative and in one case the progression was accompanied by desmin expression. KIT mutational analysis revealed the presence of distinct exon 11 mutant isoforms in all cases examined, while the same genotype was sustained in the base line and on-therapy tumour specimens, proving the common origin of analysed specimens. Conclusions: GISTs subject to imatinib treatment can undergo striking (immuno)phenotypic changes, which are not necessarily corroborated by new genotypic modifications. Because these may mimic other tumour types, this feature creates a differential diagnostic challenge, of which the pathologist should be aware.