Low Metastatic Potential Research Articles

Chondrosarcoma: biology, genetics, and epigenetics.

Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast majority of chondrosarcomas are conventional chondrosarcomas, and most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent discoveries in the biology, genetics, and epigenetics of conventional chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential therapeutic targets.

Chromosomal Aberrations Associated with Sequential Steps of the Metastatic Cascade in Colorectal Cancer Patients.

Genomic information can help to identify colorectal tumors with high and low metastatic potential, thereby improving prediction of benefit of local and/or systemic treatment. Here we investigated chromosomal aberrations in relation to the different stages of the metastatic cascade: dissemination of tumor cells into the mesenteric vein, metastatic outgrowth in the liver, intravasation of the peripheral blood circulation, and development of further distant metastasis. Peripheral and mesenteric blood from colorectal cancer patients (n = 72) were investigated for circulating tumor cells, and DNA extracted from their primary tumors was subjected to array comparative genomic hybridization profiling. The results were validated with an independent set of primary colorectal tumors (n = 53) by quantitative reverse transcription PCR. Mesenteric intravasation and liver metastasis were correlated with losses of chromosomes 16p (72%), 16q (27%), and 19 (54%), gain along 1q31 (45%) and 20q (60%), tumor cell infiltration into the peripheral blood circulation, and further distant metastasis with gain of chromosome 8q (59%) and 12 (47%, P < 0.01). Chromosome 12 gain was associated with poor overall survival in the initial (2.8 vs >7 years) and validation cohort (3.3 vs >6 years). The prospective study presented here is a hypothesis-generating study and confirmation with larger cohorts is required. This is the first study that investigated colorectal cancer in its different stages of metastasis in correlation with copy number changes of the primary tumor. This information might be helpful to identify patients with limited metastatic spread who may profit from liver metastasis resection and may lead to the discovery of new therapeutic targets.Microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE82228.

P3.CR-34 A Giant Ganglioneuroma of the Thoracic Spine

1/Case History: A 9-year old girl presented to our Department for a chronic cough. Her medical history revealed that she had pneumonia at the age of 2 years. The family history was marked by an allergic rhinitis in the father. On examination, she was afebrile.Full clinical examination revealed decreased breath sound in the left lung. 2/Investigations: Laboratory investigations were normal. The Chest CT-scan revealed a well-circumscribed mediastinal mass measuring 8.6cm*7.8cm*6.8cm. It extended through the neural foramen of T9 and also in the left chest cavity behind the aortic cross and the esophagus. Magnetic Resonance imaging showed a long intra-dural extra-medullary tumor extending from T6 to T11 levels. It extended through the left T9 neural foramen into the left thoracic cavity. The intervertebral foramen was enlarged. The thoracic aorta was totally sheathed. The lesion was mildly hypo-intense on T1-weighted imaging and heterogeneously hypo-intense on T2-weighted imaging. This radiological aspect could suggest a ganglioneuroma or a shwannoma. 3/Treatment: The multidisciplinary team decision was to perform surgery. Final histology demonstrated a well-circumscribed ganglioneuroma with negative margins. The case was reviewed at the Oncology multidisciplinary team. The decision was made to proceed with active follow-up without any adjuvant therapy given that it’s benign. The patient is currently doing well 2 years from her initial diagnosis. 4/Discussion: Thoracic intradural extra medullary Ganglioneuromas are very rare benign tumors of the autonomic nerve fibers. Most of them are incidentally discovered. In this case, our patient had no significant clinical symptoms apart from a chronic cough. The thoracic location, the potential of growth the large-size of the tumor (extending to the left chest wall with an intra-dural component) and the radiological profile, makes it therefore rare and unusual. It also illustrates the complexities of the management of this rare tumor. In fact, surgical treatment is usually safe and efficient. But, it can be more complicated in case of a such large-sized mass. So, a 2-step surgical intervention should be performed. Ganglioneuroma has commonly a good prognosis given its low-risk of recurrence and low-metastatic potential. However, it can become cancerous and spread to other organs.

Solitary Fibrous Tumors

Solitary fibrous tumors (SFTs) are a subtype of soft tissue sarcoma with fibroblastic differentiation. SFTs typically occur in patients between ages 50 and 70 and most commonly develop in the pleural space or abdomen, although they have been described in virtually every body site. Cross-sectional imaging (CT or MRI) is useful to help characterize the tumor, and core-needle biopsy is critical to obtain tissue for diagnosis. Definitive diagnosis is now made by immunohistochemical expression of STAT6, which results from a key genetic aberration (NAB2-STAT6 fusion) recently identified in SFTs. For patients with SFT, surgical resection is the mainstay of treatment. Current data suggest some benefit with adjuvant radiation therapy and systemic therapy; however, further studies are needed. After treatment, surveillance in SFT patients is important, and late recurrences have been reported. Although these tumors are generally indolent, with low metastatic potential, a subset of cases will demonstrate aggressive behavior. Simple risk assessment models have been developed to help predict clinical behavior. Novel predictive biomarkers and disease biology–driven targeted therapy options are needed. This review contains 4 figures, 2 tables and 37 references Key words: cellular angiofibroma, characteristic chromosomal translocation, dermatofibrosarcoma protuberans, Doege-Potter syndrome, hemangiopericytoma, perineuroma, preoperative angioembolization, schwannoma, solitary fibrous tumors

Solitary Fibrous Tumors

Solitary fibrous tumors (SFTs) are a subtype of soft tissue sarcoma with fibroblastic differentiation. SFTs typically occur in patients between ages 50 and 70 and most commonly develop in the pleural space or abdomen, although they have been described in virtually every body site. Cross-sectional imaging (CT or MRI) is useful to help characterize the tumor, and core-needle biopsy is critical to obtain tissue for diagnosis. Definitive diagnosis is now made by immunohistochemical expression of STAT6, which results from a key genetic aberration (NAB2-STAT6 fusion) recently identified in SFTs. For patients with SFT, surgical resection is the mainstay of treatment. Current data suggest some benefit with adjuvant radiation therapy and systemic therapy; however, further studies are needed. After treatment, surveillance in SFT patients is important, and late recurrences have been reported. Although these tumors are generally indolent, with low metastatic potential, a subset of cases will demonstrate aggressive behavior. Simple risk assessment models have been developed to help predict clinical behavior. Novel predictive biomarkers and disease biology–driven targeted therapy options are needed. This review contains 4 Figures, 2 Tables and 37 references Key words: cellular angiofibroma, characteristic chromosomal translocation, dermatofibrosarcoma protuberans, Doege-Potter syndrome, hemangiopericytoma, perineuroma, preoperative angioembolization, schwannoma, solitary fibrous tumors

CXCL12 expression is a bona fide predictor of recurrence in lung neuroendocrine tumours; a multicentric study with emphasis on atypical carcinoids- a short report.

Neuroendocrine tumors of the lung (LNETs)encompass a heterogeneous group of lesions, including tumors withno or low metastatic potential, such as typical (TCs) and atypical (ACs) carcinoids, and highly aggressive neuroendocrine carcinomas. To date, only a few biomarkers with prognostic impact have been identified in LNETs. Previous experimental studies have suggested that the cytokine CXCL12 might have a role in stratifying the outcome of lung cancer as well as LNET patients. However, the reliability of immunohistochemical (IHC) tissue expression of CXCL12 in evaluating the prognosis of resected LNETs is currently not known. Here, we subjected a cohort of 112 resected LNETs specifically enriched for ACs to IHC for CXCL12 and Ki67 using routine procedures. The clinical value of CXCL12 was assessed by applying the Cox proportional-hazards model to overall and disease-free survival rates. We found that CXCL12 was expressed in 8.3 to 38% of LNETs, depending on the different diagnostic categories. Upon survival analysis, when considering the whole cohort, we found that CXCL12-positive cases exhibited shorter disease-free survival rates compared to CXCL12-negative cases. Among ACs, tumors overexpressing CXCL12 showed significantly shorter disease-free survivalrates. Finally, we found that the Ki67 index in ACs was higher in the CXCL12-positive cases. CXCL12 immunohistochemistry may serve as a potentially useful tool to better stratify LNETs, and more specifically ACs, in clinical practice.

Horizontal transfer of exosomal CXCR4 promotes murine hepatocarcinoma cell migration, invasion and lymphangiogenesis

Exosomes have been demonstrated as an important factor to influence cancer invasion and metastasis. Previous studies have shown that CXC chemokine recepter-4 (CXCR4) and stromal cell-derived factor-1α (SDF-1α) mediates matrix metalloproteinases (MMPs) secretions to facilitate lymph node metastasis of hepatocarcinoma cells. In this study, we demonstrated that exosomes containing elevated CXCR4 from high lymph node metastatic mouse hepatocarcinoma Hca-F cells were able to promote the migration and invasion of a paired syngeneic Hca-P cells that have low metastatic potential. Such impact on enhanced migratory and invasive capacities of Hca-P cells was triggered by the internalization of exosomes isolated from Hca-F cells. This was possibly due to the horizontal transferring of CXCR4 via exosomes. The lymphatic endothelial cells (LECs) increased the migration and invasion of Hca-F cells probably by expressing SDF-1α which bound with CXCR4 in the Hca-F cells and subsequently enhanced the secretions of MMP-9, MMP-2 and vascular endothelial growth factor C (VEGF-C). Exosomal CXCR4 from Hca-F cells promoted LECs proliferative rate and lymphatic tube formation ability. Our findings suggest that horizontal transfer of exosomal CXCR4 can promote murine hepatocarcinoma cell migration, invasion and lymphangiogenesis, and exosomal CXCR4 might be a novel therapeutic target against tumor lymphatic metastasis.

Dermatofibrosarcoma Protruberans A Locally Aggressive And Recurent Malignant Tumour Of The Skin: Review And Case Report

Dermatofibrosarcoma protuberans (DFSP) is uncommon but represents one of the most common dermal sarcomas, which is said to be a locally aggressive, low grade, and relatively uncommon cutaneous tumour, which has a high propensity for local relapse with low metastatic potential. Over 90% DFSPs are genetically characterized by chromosomal rearrangements (translocation t (17;22) (q22; q13), resulting in the collagen type-1 alpha 1 (COL1A1)-platelet-derived growth factor â (PDGFB) fusion gene with well-known risk factors for developing DFSP, some cases develop at the site of previous trauma and reports have included a burn scar and the site of vaccination. The mainstay mode of treatment of DFSPs is wide local excision with traditionally 3-cm gross margins excision surgery. Mohs Micrographic Surgery (MMS) is highly recommended surgery for DFSP and is very useful treatment choice for recurrent DFSP. This case report discusses two patients with confirmed DFSP and have received adequate therapy. It also reviews salient features of evaluation and prompt management of DFSP and much emphasis on long-term follow-up of patients. Key Messages : Early diagnosis of pediatric DFSP is critical to minimize surgical disfiguration. We emphasize early evaluation of any suspicious skin lesion should not be ignored and should be excised and sent for histopathology. Undertreating a DFSP is even more problematic, as the tumour is locally destructive, can metastasize, and can prove fatal without treatment. A full metastatic workup should be done and patient should be regularly followed up, if it turns out to be malignant.

Dermatofibrosarcoma Protruberans A Locally Aggressive And Recurent Malignant Tumour Of The Skin: Review And Case Report

Dermatofibrosarcoma protuberans (DFSP) is uncommon but represents one of the most common dermal sarcomas, which is said to be a locally aggressive, low grade, and relatively uncommon cutaneous tumour, which has a high propensity for local relapse with low metastatic potential. Over 90% DFSPs are genetically characterized by chromosomal rearrangements (translocation t(17;22) (q22; q13), resulting in the collagen type-1 alpha 1 (COL1A1)-platelet-derived growth factor â (PDGFB) fusion gene with well-known risk factors for developing DFSP, some cases develop at the site of previous trauma and reports have included a burn scar and the site of vaccination. The mainstay mode of treatment of DFSPs is wide local excision with traditionally 3-cm gross margins excision surgery. Mohs Micrographic Surgery (MMS) is highly recommended surgery for DFSP and is very useful treatment choice for recurrent DFSP. This case report discusses two patients with confirmed DFSP and have received adequate therapy. It also reviews salient features of evaluation and prompt management of DFSP and much emphasis on long-term follow-up of patients. Key Messages: Early diagnosis of pediatric DFSP is critical to minimize surgical disfiguration. We emphasize early evaluation of any suspicious skin lesion should not be ignored and should be excised and sent for histopathology. Undertreating a DFSP is even more problematic, as the tumour is locally destructive, can metastasize, and can prove fatal without treatment. A full metastatic workup should be done and patient should be regularly followed up, if it turns out to be malignant.

Dermatofibrosarcoma Protruberans A Locally Aggressive And Recurent Malignant Tumour Of The Skin: Review And Case Report

Dermatofibrosarcoma protuberans (DFSP) is uncommon but represents one of the most common dermal sarcomas, which is said to be a locally aggressive, low grade, and relatively uncommon cutaneous tumour, which has a high propensity for local relapse with low metastatic potential. Over 90% DFSPs are genetically characterized by chromosomal rearrangements (translocation t (17;22) (q22; q13), resulting in the collagen type-1 alpha 1 (COL1A1)-platelet-derived growth factor â (PDGFB) fusion gene with well-known risk factors for developing DFSP, some cases develop at the site of previous trauma and reports have included a burn scar and the site of vaccination.The mainstay mode of treatment of DFSPs is wide local excision with traditionally 3-cm gross margins excision surgery. Mohs Micrographic Surgery (MMS) is highly recommended surgery for DFSP and is very useful treatment choice for recurrent DFSP.This case report discusses two patients with confirmed DFSP and have received adequate therapy. It also reviews salient features of evaluation and prompt management of DFSP and much emphasis on long-term follow-up of patients.Key Messages:Early diagnosis of pediatric DFSP is critical to minimize surgical disfiguration. We emphasize early evaluation of any suspicious skin lesion should not be ignored and should be excised and sent for histopathology. Undertreating a DFSP is even more problematic, as the tumour is locally destructive, can metastasize, and can prove fatal without treatment. A full metastatic workup should be done and patient should be regularly followed up, if it turns out to be malignant.

Atypical fibroxanthoma: Systematic review and meta-analysis of treatment with Mohs micrographic surgery or excision

Atypical fibroxanthoma (AFX) is a fibrohistiocytic tumor with relatively high local recurrence rates but low metastatic potential. Wide local excision (WLE) and Mohs micrographic surgery (MMS) are common treatments, although no consensus exists regarding optimal therapy. To systematically review evidence of AFX recurrence and metastatic rates after different surgical modalities. A comprehensive search was performed for articles published from 1946 or database inception to March 20, 2017. Studies selected included those that had 5 or more patients with atypical fibroxanthoma treated surgically. Two reviewers independently abstracted the data. Risk of bias was assessed with the Newcastle-Ottawa scale. Main outcomes and measures included recurrence and metastasis. In total, 23 studies were selected (907 patients and 914 tumors); 175 patients were treated with MMS (recurrence rate 2.0%, 95% confidence interval [CI] 0%-4.1%; metastatic rate 1.9%, 95% CI 0.1%-3.8%), and 732 were treated with WLE (recurrence rate 8.7%, 95% CI 5%-12.3%; metastasis rate 1%, 95% CI 0.2%-1.9%). Among immunocompromised patients, no recurrence or metastases developed in the MMS subgroup, although 4 of 10 recurred and 1 of 10 metastasized in the WLE subgroup. Low quality of the studies published. MMS for atypical fibroxanthoma is associated with a lower recurrence rate than WLE.

Sarcomas cutáneos: directrices para el diagnóstico y tratamiento. Dermatofibrosarcoma protuberans

Sarcomas comprise a broad group of tumors, many of whose biological behavior and aggressiveness differ from one type to another. The therapeutic approach is generally multidisciplinary and often complex. Developments in surgical and oncological dermatology during the last few decades have positioned dermatologists as specialists in the diagnosis and treatment of skin cancer. The aim of this article is to review the main soft tissue sarcomas that typically affect the skin. Dermatofibrosarcoma protuberans is a low-grade malignant sarcoma. It exhibits slow-growth, is locally invasive, and has low metastatic potential (<3%). Mohs micrographic surgery is the treatment of choice. The COL1A1-PDGFB translocation should be analyzed in cases of unclear diagnosis and when it is necessary to identify candidates for tyrosine kinase inhibitors. Imatinib is indicated for the treatment of locally advanced and metastatic dermatofibrosarcoma protuberans.

Abstract 3023: Dissecting mechanisms of breast cancer metastasis through patient-derived circulating tumor cells

Abstract During tumor progression, tumor cells invade the primary tumor microenvironment and intravasate into blood vessels, where they are referred to as circulating tumor cells (CTCs). These CTCs disseminate to other organs, and a subset of these cells will form metastasis. The growing interest for CTCs is confronted with the difficulty associated with their isolation and scarcity of material. To address this challenge, our established CTC lines from breast cancer patients offered a unique opportunity to investigate the signal pathways involved in the metastatic cascade. We assessed the metastatic potential of breast cancer patient-derived CTC lines by injecting them directly into the left ventricle of the heart in NSG mice. CTC lines are capable of generating metastases in most organs that are listed as common sites of metastases from breast cancer, such as the brain, lungs, bones and ovaries. Two patient-derived CTC lines harbored a high metastatic potential (over 80% of mice had metastases after 3 months) with generation of simultaneous metastases in the bones, lungs and ovaries. These mice remained brain-metastases free for up to 8 months. However, in 2 patient-derived CTC lines we demonstrated the brain as the preferential site of metastasis despite their low metastatic potential. Interestingly, in our mouse model, CTC lines recapitulated human cancer metastatic progression, as shown by the clinical data collected from patients where CTC lines were generated. We further investigated genetic and epigenetic determinants that regulate the organotropism of CTCs. To address this we isolated metastatic variants with a preferential tropism for the brain, lungs and bones. Investigating the gene expression signatures of metastatic variants lead us to identify the semaphorin 4D as a possible regulator of the brain metastasis. High SEMA4D expression at the primary site correlated with decreased brain metastasis-free survival in the breast cancer patients. Amplification of the chromosome 9 where the SEMA4D gene resides was also found in CTC-derived brain metastases. The SEMA4D overexpression promoted the ability of CTCs to transmigrate the blood-brain-barrier in vitro. We simultaneously investigated expression changes in stromal cells in organ-specific metastases, and among the pathways with the highest enrichment scores we found TNF and IFN signaling in the brain metastatic microenvironment. Next we used ATAC-seq to assay chromatin accessibility and identified potential regulatory factors mediating the brain metastasis formation. These data provides the evidence for the promising role of CTCs as an early prognostic factor for metastasis. Additionally, we expect to develop novel organ tropism associated markers, which can be considered for potential therapeutic targets in breast cancer. Citation Format: Remi Klotz, Amal Thomas, Sara Restrepo-Vassalli, Oihana Iriondo, Jane Han, Teng Teng, Matthew MacKay, Alan Wang, Negeen Izadian, Byoung-San Moon, Aditya Bardia, James Hicks, Andrew Smith, Min Yu. Dissecting mechanisms of breast cancer metastasis through patient-derived circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3023.

Abstract 391: Evolutionary trajectories and KRAS gene dosage define pancreatic cancer phenotypes

Abstract Pancreatic ductal adenocarcinoma (PDAC) has frequent alterations in few genes (KRAS, CDKN2A/TP53/SMAD4) and extensive heterogeneity of cancer drivers beyond. The expectation that mutational landscapes of rare drivers could explain phenotypic diversity has -with few exceptions- not come true. Likewise, PDAC metastasis is not understood, and comparisons of primary/metastasis pairs did not find recurrently mutated “metastasis genes”. Here we show that key aspects of PDAC biology are defined by gene-dosage variation of PDAC signature genes, evolving along distinct evolutionary routes. We found increased gene dosage of the initiating KRAS mutation (KRASMUT-iGD) in human PDAC precursors. Mouse models revealed the importance of KrasMUT-iGD for both, early progression and metastasis, rationalizing the high frequency of PDAC dissemination at diagnosis. To overcome limitations posed to gene dosage studies by PDAC´s stroma-richness, we developed murine cell culture resources comprising 135 primaries/metastases. Integrative analyses of their genomes, transcriptomes and tumor phenotypes, combined with human studies and functional analyses revealed a series of additional KrasMUT-dosage effects: different KrasMUT-levels define distinct cellular morphologies, histopathologies and clinical outcomes, with highest KrasMUT-expression underlying the most aggressive undifferentiated phenotypes. We also observed KrasMUT-dosage-associated cellular plasticity, including epithelial-to-mesenchymal transition. Mechanistically, oncogenic dosage-variation is linked to distinct evolutionary routes, characterized by defined types/states of tumor-suppressor alterations: Phylogenetic tracking studies revealed convergent evolution of KrasMUT-iGD-gains, with dependence on prior homozygous Cdkn2a- or Trp53-loss. By contrast, in Cdkn2aHET cancers, amplifications of known and novel oncogenes (Myc, Yap1, Nfkb2) collaborate with KrasMUT-HET to drive progression, yet with lower metastatic potential. These results also reveal oncogene-selective/context-dependent Cdkn2a-haploinsufficiency, for which Tgfβ pathway alterations provide permissiveness. Our study uncovers universal principles underlying PDAC biology and phenotypic diversification. It describes evolutionary trajectories, identifies their genetic hallmarks and shows how oncogenic dosage-variation is differentially licensed along individual routes to control critical disease characteristics, including early progression, histopathology, metastasis, cellular plasticity and clinical aggressiveness. Citation Format: Sebastian Mueller, Thomas Engleitner, Roman Maresch, Magdalena Zukowska, Sebastian Lange, Thorsten Kaltenbacher, Björn Konukiewitz, Rupert Öllinger, Maximilian Zwiebel, Alex Strong, Hsi-Yu Yen, Ruby Banerjee, Sandra Louzada, Beiyuan Fu, Barbara Seidler, Juliana Götzfried, Kathleen Schuck, Zonera Hassan, Nina Schönhuber, Sabine Klein, Christian Veltkamp, Mathias Friedrich, Lena Rad, Maxim Barenboim, Christoph Ziegenhain, Julia Hess, Oliver M. Dovey, Stefan Eser, Swati Parekh, Fernando Constantino-Casas, Jorge de la Rosa, Marta I. Sierra, Mario Fraga, Julia Mayerle, Günter Klöppel, Roland M. Schmid, Juan Cadiñanos, Pentao Liu, George Vassiliou, Wilko Weichert, Katja Steiger, Wolfgang Enard, Fengtang Yang, Kristian Unger, Günter Schneider, Ignacio Varela, Allan Bradley, Dieter Saur, Roland Rad. Evolutionary trajectories and KRAS gene dosage define pancreatic cancer phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 391.

Lentiviral-mediated microRNA-26b up-regulation inhibits proliferation and migration of hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a frequently occurred malignancy worldwide with a high mortality. The treatment for HCC is still controversial. Emerging evidences have demonstrated that microRNAs (miRs) play a role in HCC. This study aims to investigate the effects of lentiviral-mediated miRNA-26b (miR-26b) on the proliferation and metastasis of HCC cells. The normal hepatic cell line HL-7702 and HCC cell lines HepG2 (without metastatic potential), SMMC-7721 (with low metastatic potential) and MHCC97H (with high metastatic potential) were purchased for our experiment. The lentiviral-mediated miR-26b overexpression (miR-26b-LV) and low expression (sh-miR-26b) were constructed to transfect the cells. The miR-26b expression and expressions of Karyopherin α-2 (KPNA2), matrix metalloproteinase 1 (MMP-1), MMP-7 and MMP-14 were determined by RT-qPCR and western blot analysis. The proliferation and metastasis of transfected HCC cells were detected by MTT and Transwell assay respectively. The miR-26b expressions were decreased significantly in MHCC97H cells. With lentiviral-mediated miR-26b overexpression, the proliferation and migration of HepG2, MHCC97H and SMMC-7721 cells were decreased significantly. The RT-qPCR and western blot analysis results revealed that the mRNA and protein expressions of KPNA2, MMP-1, MMP-7 and MMP-14 were decreased by lentiviral-mediated miR-26b overexpression. All the above indexes in the HepG2, MHCC97H and SMMC-7721 cells treated by sh-miR-26b exhibited opposite trends. These results show that overexpressed miR-26b could inhibit the proliferation and metastasis of HCC cells significantly, which provides a novel target and theoretical foundation for the treatment of HCC.

Recurrent Solid Pseudopapillary Neoplasm of Pancreas: Case Report and Review of Literature.

Background: Solid pseudopapillary neoplasm of pancreas is a rare tumor with a low potential for metastasis and recurrence. Long-term outcomes after surgical resection are excellent and recurrences after an R0 resection are extremely rare.Case Presentation: We present an unusual case of a 42-year-old man who had a recurrence of his solid pseudopapillary tumor 4 years after undergoing a distal pancreatectomy and splenectomy and then again a year after his reresection.Conclusions: The lack of histological features deemed to be suggestive of a malignant variant and the aggressive clinical course seen in this case is remarkable. It underscores the fact that despite the low incidence, recurrences of solid pseudopapillary neoplasms of the pancreas do occur and it can be very difficult to predict malignant potential based on radiological or histopathological features.

SERPINA3 Silencing Inhibits the Migration, Invasion, and Liver Metastasis of Colon Cancer Cells.

To investigate the impact of SERPINA3 on the migration, invasion, and liver metastasis of colon cancer cells. Immunohistochemical staining was conducted to determine SERPINA3 expression in the cancer and adjacent normal tissues of 131 patients suffering from colon cancer. In vitro experiment, colon cancer cells with low (HT-29P), intermediate (KM-12C), and high (HT-29LMM, KM-12L4) metastatic potential were obtained to examine SERPINA3 expression levels. Besides, quantitative real-time PCR (qRT-PCR) and Western Blot were performed to detect SERPINA3 expression in HT-29LMM and KM-12L4 cells transfected with SERPINA3 siRNA; Wound-healing and Transwell assays to measure cell migration and invasion, respectively; and ELISA to detect MMP-2 and MMP-9 levels. In vivo experiment, mice with liver metastasis of colon cancer were established to observe the effect of SERPINA3 silencing on liver metastasis. Immunohistochemical assay was applied to evaluate the expressions of Serpina3, Mmp-2, Mmp-9, and proliferating cell nuclear antigen (Pcna) in liver metastasis tissues. SERPINA3 in colon cancer tissues was higher than in adjacent normal tissues, which was associated with patients' clinicopathological features. Besides, SERPINA3 expression showed a rising trend in low, intermediate, and high metastatic potential colon cancer cells. After KM-12L4 and HT-29LMM cells transfected with SERPINA3 siRNA, the migration and invasive ability of cells, as well as the expression levels of MMP-2 and MMP-9 were all decreased. Moreover, SERPINA3 siRNA could not only reduce live metastasis of mice, but also down-regulate the expression of Mmp-2 and Mmp-9 in liver metastasis tissues. SERPINA3 silencing could inhibit the migration, invasion, and liver metastasis of colon cancer cells.

High co-expression of the SDF1/CXCR4 axis in hepatocarcinoma cells is regulated by AnnexinA7 in vitro and in vivo

BackgroundSDF1/CXCR4 and AnnexinA7 play important roles in many physiological and pathological conditions, but the molecular association between them in cancer cells has not been studied thus far.MethodsThe expression changes of SDF1/CXCR4 were detected by gene transcriptome sequencing, qRT-PCR, Western blotting, cytoimmunofluorescence and immunohistochemistry in mouse hepatocarcinoma F/P cells, AnnexinA7 downregulated expression F (FA7DOWN) cells, AnnexinA7 overexpression P (PA7UP) cells, AnnexinA7 unrelated sequence F (FSHUS) cells, empty vector P (PNCEV) cells and normal liver cells in vitro and in vivo.ResultsSDF1 and CXCR4 were co-expressed in hepatocarcinoma cells. SDF1 was localized mainly in the cytoplasm of cells, while CXCR4 was mainly localized in the cell membrane. Both in vitro and in vivo, expression levels of SDF1/CXCR4 in F and P cells were higher than in normal liver cells, and expression levels of SDF1/CXCR4 in F cells with high lymphatic metastatic potential were higher than those in P cells with low lymphatic metastatic potential. Expression of SDF1 was higher than that of CXCR4 in P cells and normal liver cells, while expression of CXCR4 was higher than that of SDF1 in F cells. Expression levels of SDF1/CXCR4 were completely consistent with AnnexinA7 regulation. After the AnnexinA7 gene was downregulated or upregulated, expression levels of SDF1/CXCR4 in FA7DOWN/PA7UP cells were lower or higher than those in FSHUS/PNCEV cells. Furthermore, CXCR4 was more sensitively modulated by AnnexinA7 regulation than SDF1.ConclusionsHigh co-expression of SDF1/CXCR4 is a molecular characteristic of hepatocarcinoma cells, especially those with high lymphatic metastatic potential. AnnexinA7 positively regulates expression levels of SDF1/CXCR4, in particular CXCR4, and AnnexinA7 is a functional regulator of SDF1/CXCR4.

MiR-203 inhibits lung cancer cell metastasis by targeting fatty acid binding protein 4

To explore the role of fatty acid binding protein 4 (FABP4) in regulating lung cancer cell metastasis and identify miRNAs that target FABP4. The expression of FABP4 in lung cancer cells with different metastatic potentials was detected using enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effects of FABP4 knockdown or overexpression by shRNA or a recombinant lentivirus, respectively, on lung cancer cells metastasis were assessed. The miRNAs that targeted FABP4 were screened using target prediction algorithms and the results were verified with Q-PCR. FABP4 expression was significantly higher in lung cancer cell lines with high metastatic potentials (NL9980, H661, and 95C) than in those with low metastatic potentials (L9981, A549, and PC13) (P<0.05). FABP4 knockdown in NL9980 cells resulted in significantly inhibited metastasis of the cells (P<0.05), while FABP4 overexpression obviously promoted the metastasis of A549 cells (P<0.05). The expressions of miR-203, miR-361 and miR-539 were significantly higher in highly metastatic lung cancer cells than in the cells with low metastatic potentials (P<0.05). In NL9980 cells, FABP4 expression was most obviously suppressed by miR-203 (P<0.05), and target site mutational FABP4 overexpression significantly attenuated the inhibitory effect of miR-203 on NL9980 metastasis (P<0.05). FABP4 can promote lung cancer metastasis, and by targeting FABP4 to inhibit its expression, miR-203 can suppress the metastasis of lung cancer cells.

PD51-01 MANAGEMENT OF GENETICALLY DEFINED RENAL TUMORS UTILIZING SIZE-BASED RISK STRATIFICATION: LONG-TERM RESULTS

You have accessJournal of UrologyKidney Cancer: Localized: Active Surveillance1 Apr 2018PD51-01 MANAGEMENT OF GENETICALLY DEFINED RENAL TUMORS UTILIZING SIZE-BASED RISK STRATIFICATION: LONG-TERM RESULTS Mark Ball, Julie An, James Peteron, Maria Merino, Ramaprasad Srinivasan, Adam Metwalli, and W. Marston Linehan Mark BallMark Ball More articles by this author , Julie AnJulie An More articles by this author , James PeteronJames Peteron More articles by this author , Maria MerinoMaria Merino More articles by this author , Ramaprasad SrinivasanRamaprasad Srinivasan More articles by this author , Adam MetwalliAdam Metwalli More articles by this author , and W. Marston LinehanW. Marston Linehan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2341AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Genetically defined renal cell carcinomas, including those associated with von Hippel-Lindau (VHL; clear cell RCC, VHL gene), Hereditary Papillary Renal Carcinoma (HPRC, Type 1 Papillary RCC, MET gene) Birt-Hogg-Dubé (BHD, chromophobe RCC, FLCN gene), Hereditary Leiomyomatosis and Renal Cell Carcinomas (HLRCC; Type 2 Papillary RCC, Fumarate Hydratase gene) and Succinate Dehydrogenase RCC (SDHRCC, eosinophilic RCC, SDHB gene) are managed at our institution based on genotype. While metastasis may develop with small (< 3 cm) HLRCC or SDHRCC renal tumors, based on early observations of low metastatic potential of small lesions renal lesions in VHL, HPRC and BHD, these patients have been managed with active surveillance until the largest tumor reaches 3 cm, at which time surgical resection of ipsilateral tumors is recommended. The present study was performed in order to evaluate the oncologic efficacy of the 3 cm size threshold with in a cohort of VHL, HPRC and BHD patients with long-term follow-up. METHODS Patients managed on prospective National Cancer Institute Institutional Review-approved protocols with VHL-, HPRC- and BHD-associated solid renal masses were identified. The diameter of the largest solid tumor, the length of follow-up, the presence of metastatic disease was evaluated. The proportion of patients who developed metastatic disease at size thresholds beyond 3 cm was assessed in 1 cm increments. Metastasis-free survival (MFS) was defined as the interval from initial screening to development of metastatic disease. RESULTS A total of 634 patients with genetically defined RCC were identified, including 440 with VHL-, 43 with HPRC- and 151 with BHD-associated renal tumors. While metastatic disease was found to have developed in 42 patients (10.1%) with VHL-, 6 (14%) with HPRC-, and 8 (5.3%) with BHD-associated RCC, to date, no patient who underwent surgical resection when the largest tumor was < 3 cm has yet developed metastatic disease. Table 1 lists the proportion of patients who developed metastases by size of their largest tumor. MFS for VHL patients whose renal tumors were resected when they reached 3 cm threshold was significantly longer compared to those who were not (p=0.007). The 5, 10 and 20-year MFS for patients whose tumors had not been resected when they reached the 3 cm threshold was 95.7%, 91.1%, and 69.5%, respectively. CONCLUSIONS In a cohort of 634 patients with VHL-, HPRC- and BHD-associated RCC adherence to the 3 cm guideline was associated with superior MFS compared to those who were not. In addition, these findings may have broad applicability for the management of non-hereditary genetically defined renal tumors. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e975 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Mark Ball More articles by this author Julie An More articles by this author James Peteron More articles by this author Maria Merino More articles by this author Ramaprasad Srinivasan More articles by this author Adam Metwalli More articles by this author W. Marston Linehan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...