Invasive Behavior Research Articles

Prevalence and clinical characteristics of Crooke's cell adenomas in 101 patients with T-PIT-positive pituitary adenomas: Case series and literature review.

PurposeWe aimed to perform a retrospective analysis of a rare subtype of corticotroph adenoma, Crooke’s cell adenoma, to better understand its clinical features.MethodsWe collected T-PIT-positive pituitary adenomas and screened Crooke’s cell adenomas from January 2020 to December 2021 in our center. Case reports of such tumors were also collected through a literature search. Clinical data such as biochemical tests, imaging examinations, and pathological data of the above cases were analyzed.ResultsA total of 101 T-PIT-positive patients were treated in our center in the last 2 years, and 4 were finally pathologically diagnosed with Crooke’s cell adenomas. All of these patients were male with elevated adrenocorticotropic hormone levels, and 50.0% presented with hypercortisolemia, Cushing’s syndrome, visual impairment, and headache. The tumor diameter was significantly larger in these 4 patients (37.0 mm) than in the other patients (26.0 mm), and their tumor invasive behavior was more pronounced. Cases reported in the literature were mainly female (72.8%), and the clinical presentation was also dominated by Cushing’s syndrome (65.1%) and hormonal dysfunction. Tumors were more common as macroadenomas (33.2 mm) and suprasellar growths (63.8%). The tumor recurrence rate was as high as 55.6%, with 6 cases progressing to pituitary carcinomas and 7.7% of tumor-related deaths. Our further integrated analysis of our center and reported cases revealed that gender, Cushing’s syndrome, visual dysfunction, hormonal disorders, and tumor growth characteristics were statistically different in different tumor categories.ConclusionCrooke’s cell adenoma is a tumor subtype with obvious clinical aggressive behavior, and an in-depth analysis of its clinical characteristics may assist in developing a comprehensive treatment plan.

Preoperative prediction of invasive behavior of pancreatic solid pseudopapillary neoplasm by MRI-based multiparametric radiomics models.

A log-combined model was developed to predict the invasive behavior of pancreatic solid pseudopapillary neoplasm (pSPN) based on clinical and radiomic features extracted from multiparametric magnetic resonance imaging (MRI). A total of 111 patients with pathologically confirmed pSPN who underwent preoperative plain and contrast-enhanced MRI were included, and divided into an invasive group (n = 34) and non-invasive group (n = 77). Clinical features and laboratory data related to pSPN invasive behavior were analyzed. Regions of interest were delineated based on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1WI (CE-T1WI) to extract radiomic features. Correlation analysis was performed for these features, followed by L1_based feature selection (C = 0.15). A logistic regression algorithm was used to construct models based on each of the four sequences and a log-combined model was used to integrate the sequences. A receiver operating characteristic (ROC) curve was plotted to evaluate the model performance, and the Brier score was used to assess the overall accuracy of the model predictions. The area under the ROC curve was 0.68, 0.73, 0.71, and 0.49 for Log-T1WI, Log-T2WI, Log-DWI, and Log-CE models, respectively, and 0.81 for the log-combined model. The accuracy, precision, sensitivity, and specificity of the log-combined model were 0.77, 0.88, 0.75, and 0.78, respectively. The best performance was obtained with the log-combined model with a Brier score of 0.18. Tumor location was identified as a significant clinical feature in comparison between the two groups (p < 0.05), and invasive pSPN was more frequent in the tail of the pancreas. The log-combined model based on multiparametric MRI and clinical features can be used as a non-invasive diagnostic tool for preoperative prediction of pSPN invasive behavior and to facilitate the development of individualized treatment strategies and monitoring management plans.

A RARE CASE OF JUVENILE OSSIFYING TRABECULAR FIBROMA IN THE MANDIBLE

A 12-year-old male patient reported to the oral medicine care unit complaining of an enlarged face. Clinical and radiographic examinations revealed a lesion in the left mandibular body causing expansion of the cortical bone. Laboratory blood tests showed high levels of eosinophils and lymphocytes. Computed tomography showed cortical bone remodeling in the body of the mandible due to an osteolytic lesion with areas of cortical discontinuity. Incisional biopsy revealed the diagnosis of juvenile ossifying fibroma trabecular. Conservative enucleation of the lesion was executed. Immunohistochemistry was performed on the surgical specimen, which ruled out the possibility of low-grade osteosarcoma and confirmed the previous diagnosis. One year and 2 months after the procedure, the panoramic x-ray of follow-up control showed bone neoformation; however, bone expansion was still detected. Juvenile ossifying fibroma is a rare lesion with an invasive behavior and, in most cases, occurs in the jaw. A 12-year-old male patient reported to the oral medicine care unit complaining of an enlarged face. Clinical and radiographic examinations revealed a lesion in the left mandibular body causing expansion of the cortical bone. Laboratory blood tests showed high levels of eosinophils and lymphocytes. Computed tomography showed cortical bone remodeling in the body of the mandible due to an osteolytic lesion with areas of cortical discontinuity. Incisional biopsy revealed the diagnosis of juvenile ossifying fibroma trabecular. Conservative enucleation of the lesion was executed. Immunohistochemistry was performed on the surgical specimen, which ruled out the possibility of low-grade osteosarcoma and confirmed the previous diagnosis. One year and 2 months after the procedure, the panoramic x-ray of follow-up control showed bone neoformation; however, bone expansion was still detected. Juvenile ossifying fibroma is a rare lesion with an invasive behavior and, in most cases, occurs in the jaw.

CROSS-TALK OF PROTEINS RELATED TO INVADOPODIA AND THE INVASION PROCESS IN SALIVARY GLAND MUCOEPIDERMOID CARCINOMA

<h3>Objectives</h3> To evaluate the immunoexpression of Tks4, Tks5, cortactin, and MT1-MMP proteins in salivary gland mucoepidermoid carcinoma (MEC). <h3>Study Design</h3> Immunohistochemistry was performed to compare the expression of the 4 proteins in samples of MEC (<i>n</i> = 19) and healthy salivary glands (SG) (<i>n</i> = 10). The immunostaining assessment was performed by measuring the area (in µm) and the fraction (in %) of immunostaining of antibodies using the software ImageJ. The data were statistically analyzed using the Kruskal-Wallis test with Dunn's post hoc test for different proteins. Spearman correlation test was also performed. <h3>Results</h3> All MEC samples expressed Tks4, Tks5, cortactin, and MT1-MMP. There was a high immunoexpression of the 4 proteins in the MEC samples compared with the SG samples (*<i>P</i> < .05). In neoplastic MEC cells, expression of Tks4 and Tks5 proteins was correlated (*<i>P</i> < .05). <h3>Conclusions</h3> From the data obtained and in view of the important role of these proteins in the formation of invadopodia and in the cell invasion process, the expression of these proteins together in the MEC, as well as the correlation of Tks4 and Tks5, may suggest a possible relationship between these proteins and the invasive behavior of this neoplasm.

Introducing Wound Healing Assays in the Undergraduate Biology Laboratory Using Ibidi Plates.

ABSTRACTThe wound healing assay is a simple and inexpensive method that allows researchers to experimentally mimic cell growth and migration leading to wound healing. In this assay, a wound is created on a monolayer of cultured mammalian cells and cell migration is monitored. Micrographs are captured at regular intervals during the duration of the experiment. These microscopy images are analyzed to compare cell migration and wound closure under different conditions. Introduction of different cytotoxic treatments into a wound healing assay can provide information as to whether a particular drug or compound of interest has the ability to affect cell migration. This type of analysis is important when assessing the ability of a particular cancer cell line to display invasive and metastatic behaviors. One of the challenges of this assay is to create the original wound in a way that is consistent across plates or treatments, facilitating comparisons across experimental groups. This is a particular challenge when using the wound healing assay in the context of an undergraduate biology class to expose students to a distinct form of mammalian cell culture and help them apply scientific knowledge and research skills. We found an easy way to overcome this obstacle by using ibidi plates. In this article, we provide a simple protocol to use ibidi plates and HeLa cells to set up wound healing assays. This laboratory exercise allows undergraduate students to utilize different skills developed through cell culture experience, such as growing, treating, and imaging mammalian cells.

MicroRNA192 Promotes Metastasis and Invasion of Breast Cancer via Targeting Tensin1 and Enhancing Cell Division Control Protein 42 Homolog (CDC42) Expression

We aimed to dissect the biological impacts and mechanisms of MicroRNA192 in breast cancer metastasis and invasion. Tumor tissues from patients and breast cancer cells were used to measure miR-192 level via RT-PCR. The miR-192 mimics, miR-192 inhibitor, si-Tensin1 and corresponding negative controls were transfected into cells followed by analysis of cell invasion by transwell assay and CDC42 level by western blot. Afterwards, a tumor transplantation model was established to assess the malignancy progression and migration. The human miR-192 accounted for approximately 14% of those overexpressed miRNAs. Overexpression of miR-192 promoted malignant cell invasion, while knockdown of endogenous miR-192 significantly decreased cell invasion, which suggested that miR-192 could exert a promotive factor in the invasive characteristic of breast cancer cells in vitro. In contrast to control group, tumor metastasis was significantly provoked in the miR-192 overexpression group. miR-192 directly targeted and suppressed the expression of Tensin1. miR-192 enhanced the malignant invasiveness by regulating Cdc42 and was corrected with correlation with the survival of patients. High miR-192 level is related to the malignant invasiveness and metastatic behavior, as well as the poor prognosis of patients with breast cancer via activating Cdc42 and targeting Tensin1.

Catulin reporter marks a heterogeneous population of invasive breast cancer cells with some demonstrating plasticity and participating in vascular mimicry

Breast cancer is the most commonly diagnosed cancer in women worldwide. The activation of partial or more complete epithelial–mesenchymal transition in cancer cells enhances acquisition of invasive behaviors and expands their generation of cancer stem cells. Increased by EMT plasticity of tumor cells could promote vascular mimicry, a newly defined pattern of tumor microvascularization by which aggressive tumor cells can form vessel-like structures themselves. VM is strongly associated with a poor prognosis, but biological features of tumor cells that form VM remains unknown. Here we show that catulin is expressed in human BC samples and its expression correlates with the tumor progression. Ablation of catulin in hBC cell lines decreases their invasive potential in the 3D assays. Using a novel catulin promoter based reporter we tracked and characterized the small population of invasive BC cells in xenograft model. RNAseq analysis revealed enrichment in genes important for cellular movement, invasion and interestingly for tumor-vasculature interactions. Analysis of tumors unveiled that catulin reporter marks not only invasive cancer cells but also rare population of plastic, MCAM positive cancer cells that participate in vascular mimicry. Ablation of catulin in the xenograft model revealed deregulation of genes involved in cellular movement, and adhesive properties with striking decrease in CD44 which may impact stemness potential, and plasticity of breast cancer cells. These findings show directly that some plastic tumor cells can change the fate into endothelial-like, expressing MCAM and emphasize the importance of catulin in this process and breast cancer progression.

Spatiotemporal gating of Stat nuclear influx by Drosophila Npas4 in collective cell migration.

Collective migration is important to embryonic development and cancer metastasis, but migratory and nonmigratory cell fate discrimination by differential activity of signal pathways remains elusive. In Drosophila oogenesis, Jak/Stat signaling patterns the epithelial cell fates in early egg chambers but later renders motility to clustered border cells. How Jak/Stat signal spatiotemporally switches static epithelia to motile cells is largely unknown. We report that a nuclear protein, Dysfusion, resides on the inner nuclear membrane and interacts with importin α/β and Nup153 to modulate Jak/Stat signal by attenuating Stat nuclear import. Dysfusion is ubiquitously expressed in oogenesis but specifically down-regulated in border cells when migrating. Increase of nuclear Stat by Dysfusion down-regulation triggers invasive cell behavior and maintains persistent motility. Mammalian homolog of Dysfusion (NPAS4) also negatively regulates the nuclear accumulation of STAT3 and cancer cell migration. Thus, our finding demonstrates that Dysfusion-dependent gating mechanism is conserved and may serve as a therapeutic target for Stat-mediated cancer metastasis.

A Case of Primary Dermatofibrosarcoma Protuberans of the Lower Anterior Abdominal Wall Treated by Abdominoplasty

Dermatofibrosarcoma protuberans is a rare skin neoplasm with a high recurrence rate and a local invasive behavior. Excisional surgery is the mainstay of treatment of such tumors. Obtaining an adequate surgical safety margin is essential to ensure radical excision, however this may result in extensive skin and soft tissue defects that may require resurfacing. In this clinical case report, we describe a case of a large DFSP of the lower anterior abdominal wall, treated by abdominoplasty, we also perform a relevant scoping literature review on the topic.

Loss of Frizzled 9 in Lung Cells Alters Epithelial Phenotype and Promotes Premalignant Lesion Development.

The transmembrane receptor Frizzled 9 (FZD9) is important for fetal neurologic and bone development through both canonical and non-canonical WNT/FZD signaling. In the adult lung, however, Fzd9 helps to maintain a normal epithelium by signaling through peroxisome proliferator activated receptor γ (PPARγ). The effect of FZD9 loss on normal lung epithelial cells and regulators of its expression in the lung are unknown. We knocked down FZD9 in human bronchial epithelial cell (HBEC) lines and found that downstream EMT targets and PPARγ activity are altered. We used a FZD9-/- mouse in the urethane lung adenocarcinoma model and found FZD9-/- adenomas had more proliferation, increased EMT signaling, decreased activation of PPARγ, increased expression of lung cancer associated genes, increased transformed growth, and increased potential for invasive behavior. We identified PPARγ as a transcriptional regulator of FZD9. We also demonstrated that extended cigarette smoke exposure in HBEC leads to decreased FZD9 expression, decreased activation of PPARγ, and increased transformed growth, and found that higher exposure to cigarette smoke in human lungs leads to decreased FZD9 expression. These results provide evidence for the role of FZD9 in lung epithelial maintenance and in smoking related malignant transformation. We identified the first transcriptional regulator of FZD9 in the lung and found FZD9 negative lesions are more dangerous. Loss of FZD9 creates a permissive environment for development of premalignant lung lesions, making it a potential target for intervention.

Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer.

The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies - MUC CRCs either display a conventional 'apical-in' polarity or, more frequently, harbor an inverted 'apical-out' topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFβ and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.

Biochemical composition, nutritional value and socio-economic impacts of the invasive crab Callinectes sapidus Rathbun, 1896 in central Mediterranean Sea

The Atlantic crab Callinectes sapidus was recently recorded in Tunisia and presents an invasive behavior. This study aims to evaluate its socio-economic impacts on small-scale fisheries and to analyze variations in chemical composition, fatty acids profile, and nutritive value according to sex and edible tissues. Socio-economic surveys via face-to-face revealed a decline in fishermen’s income from 15% to even 70% (damages on fishing nets and catches). Muscles yield of Callinectes sapidus ranged between 36.07±2.84% and 42.83±6.53% respectively for females and males. All the analyzed tissues contained high protein contents (&gt; 23%) and particularly cephalothorax muscles reaching 27.05±0.16%. This new exotic food can be recommended in low fat diets since it contained less than 5% of total fats. The fatty acid profile was dominated by the polyunsaturated fatty acids (PUFA) for both sexes and all the analyzed tissues. Eicosapentaenoic acid, docosahexaenoic acid and arachidonic acid were the most abundant PUFA in all tissues ranging respectively from 9.31% to 15.64%, from 8.74% to 13.78% and between 6.81% and 9.21%. All the nutritional indexes of lipids indicated that this crab could be beneficial for human health. In addition, it constitutes a new marine resource with high economic opportunity.

Ecological features of the alien species Pistia stratiotes L. in different habitats of the secondary distribution range (Ukraine)

Abstract We have analyzed structural and dynamic characteristics (production, morphometric parameters, phytocoenotic features and invasive behavior) of two locations with the alien species Pistia stratiotes L. in different types of water bodies, by origin, use and trophic status (a drainage canal and oxbow lake) in the outskirts of Kyiv. It is possible that in the case of increased anthropogenic eutrophication due to inorganic nitrogen, mother plants become smaller and more compact. The variability of morphological features increases. We also have distinguished growth of invasive potential of the species in the conditions of the water bodies of the region.

Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition

Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, although they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. In this study, we demonstrate a molecular mechanism for cell fate switching during epithelial cell competition. We found that during competition within epithelial cell layers, Src transformation promotes maturation of focal adhesions and degradation of extracellular matrix. Src-transformed cells underwent basal delamination by Src activation within sphingolipid/cholesterol-enriched membrane microdomains/lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. A comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB-domain-containing protein 1 (CDCP1) was identified as an Src-activating scaffold and as a Met regulator in lipid rafts, and its overexpression induced basal delamination. In renal cancer models, CDCP1 promoted epithelial-mesenchymal transition-mediated invasive behavior by activating the Src-STAT3-MMP axis through Met activation. Overall, these results suggest that spatial activation of Src signaling in lipid rafts confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside.

Simple SummaryTumor hypoxia remains a significant problem in the effective treatment of most cancers. Tumor cells within hypoxic niches tend to be largely resistant to most therapeutic modalities, and adaptation of the cells within the hypoxic microenvironment imparts the cells with aggressive, invasive behavior. Thus, a major goal of successful cancer therapy should be the eradication of hypoxic tumor cells. Carbonic Anhydrase IX (CAIX) is an exquisitely hypoxia induced protein, selectively expressed on hypoxic tumor cells, and thus has garnered significant attention as a therapeutic target. In this Commentary, we discuss the current status of targeting CAIX, and future strategies for effective, durable cancer treatment.Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy.

Early-stage colon cancer with high MALAT1 expression is associated with the 5-Fluorouracil resistance and future metastasis.

This study aimed to investigate the role of long noncoding RNA (LncRNA) expression profiles to predict relapse and 5-FU response in patients with stage I/II colon cancer (CC). The expression level of 15 LncRNA was analyzed in stage I/II colon tumors of 126 CC patients. To confirm the findings in-vitro, 5FU-resistant HT29 cells were generated by subjecting HT-29 cells to the increasing concentrations of 5FU for 6months. The 5FU resistance was observed in WST-1 and Annexin V analyses. The colony formation and wound healing assays were assessed to determine the metastatic properties of the cells. Expression levels of LncRNAs and mRNA of EMT-related genes were determined by RT-PCR. The role of LncRNA on metastasis and 5FU sensitivity were confirmed in pcDNA3.0-PTENP1 and si-MALAT1 expressed 5FU-resistant HT29 cell lineages. High MALAT1 (p = 0.0002) and low PTENP1 (p = 0.0044) expressions were significantly associated with 5-FU resistance and tumor relapse in stage I/II CC. The invasiveness and colony-forming characteristics of 5-FU-resistant cell lineages were higher as compared to the parent HT-29. Moreover, the expression of MALAT1 (p = 0.0009) was increased while the expression of PTENP1 (p = 0.0158) decreased in 5FU-resistant-HT-29 cells. Si-MALAT1 treatment increased cell sensitivity to 5FU, whereas it decreased invasive behaviors of 5 FU-resistant-HT-29 cells. MALAT1 may be a biomarker in predicting recurrence in early-stage CC. Our findings suggest that a cell-based therapy to target MALAT1 could be established for these patients to prevent metastasis and 5-FU resistance.

When Does Competitive Learning Occur? The Impact of Alliance Network Embeddedness on Technological Invasion

AbstractFirms participate in an alliance network to collaborate for specific goals and common values; however, the network situation and the interaction between partnering firms enable them to appropriate their partners’ proprietary knowledge and adopt competitive actions. Little is known about whether and when the focal firm would invade its partner's technological domains in alliance networks. We examined how relational embeddedness and positional embeddedness influence the focal firm's technological invasion behaviour against its partner, and the moderating role of relative alliance experience. Although previous studies have emphasized that a central position would enhance firms’ competitive aggression, we argue that this central position imposes more constraints on firms’ competitive behaviour. The empirical results show a U‐shaped relationship between relational embeddedness and technological invasion, while relative centrality negatively affects technological invasion behaviour and negatively moderates the U‐shaped relationship. Furthermore, the results indicate that relative alliance experience attenuates the U‐shaped relationship between relational embeddedness and technological invasion, while it enhances the negative effect of relative centrality on technological invasion. These findings provide new insights and perspectives to study the coopetition phenomenon in alliance networks.

A diagnostic approach to paratesticular lesions with tubulopapillary architecture: a series of 16 serous borderline tumors/low-grade serous carcinoma and 14 well-differentiated papillary mesothelial tumors and mesothelioma

As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n=15), low-grade serous carcinoma (n=1), well-differentiated papillary mesothelial tumors (WDPMTs; n=2), and mesothelioma (n=12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.

Inhibition of L-type voltage-gated calcium channel-mediated Ca2+ influx suppresses the collective migration and invasion of ameloblastoma.

Ameloblastoma (AM) has been known as a benign but locally invasive tumour with high recurrence rates. Invasive behaviour of the AM results in destruction of the adjacent jawbone and the non-detectable remnants during surgery, interrupting the complete elimination of cancer cells. To explore novel targets for the tumour cell invasion, a transcriptomic analysis between AM and odontogenic keratocyst were performed through next-generation sequencing in detail. Enrichment of CACNA1C gene (encoding Cav1.2) in AM, a subunit of the L-type voltage-gated calcium channel (VGCC) was observed for the first time. The expression and channel activity of Cav1.2 was confirmed by immunostaining and calcium imaging in the patient samples or primary cells. Verapamil, L-type VGCC blocker revealed suppression of the Ca2+ -induced cell aggregation and collective invasion of AM cells in vitro. Furthermore, the effect of verapamil in suppressing AM invasion into the adjacent bone was confirmed through orthotopic xenograft model specifically. Taken together, Cav1.2 maybe considered to be a therapeutic candidate to decrease the collective migration and invasion of AM.

Pasireotide-Induced Shrinkage in GH and ACTH Secreting Pituitary Adenoma: A Systematic Review and Meta-Analysis.

IntroductionPasireotide (PAS) is a novel somatostatin receptor ligands (SRL), used in controlling hormonal hypersecretion in both acromegaly and Cushing’s Disease (CD). In previous studies and meta-analysis, first-generation SRLs were reported to be able to induce significant tumor shrinkage only in somatotroph adenomas. This systematic review and meta-analysis aim to summarize the effect of PAS on the shrinkage of the pituitary adenomas in patients with acromegaly or CD.Materials and methodsWe searched the Medline database for original studies in patients with acromegaly or CD receiving PAS as monotherapy, that assessed the proportion of significant tumor shrinkage in their series. After data extraction and analysis, a random-effect model was used to estimate pooled effects. Quality assessment was performed with a modified Joanna Briggs’s Institute tool and the risk of publication bias was addressed through Egger’s regression and the three-parameter selection model.ResultsThe electronic search identified 179 and 122 articles respectively for acromegaly and CD. After study selection, six studies considering patients with acromegaly and three with CD fulfilled the eligibility criteria. Overall, 37.7% (95%CI: [18.7%; 61.5%]) of acromegalic patients and 41.2% (95%CI: [22.9%; 62.3%]) of CD patients achieved significant tumor shrinkage. We identified high heterogeneity, especially in acromegaly (I2 of 90% for acromegaly and 47% for CD), according to the low number of studies included.DiscussionPAS treatment is effective in reducing tumor size, especially in acromegalic patients. This result strengthens the role of PAS treatment in pituitary adenomas, particularly in those with an invasive behavior, with progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue.Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022328152, identifier CRD42022328152