A patient organization perspective: charting the course to a cure for SCN2A-related disorders.

The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction in Nav1.

Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning.

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools.

Propranolol Sensitizes Vascular Sarcoma Cells to Doxorubicin by Altering Lysosomal Drug Sequestration and Drug Efflux.

Angiosarcoma is a rare cancer of blood vessel-forming cells with a high patient mortality and few treatment options. Although chemotherapy often produces initial clinical responses, outcomes remain poor, largely due to the development of drug resistance. We previously identified a subset of doxorubicin-resistant cells in human angiosarcoma and canine hemangiosarcoma cell lines that exhibit high lysosomal accumulation of doxorubicin.

Correction: Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment.

[This corrects the article DOI: 10.18632/oncoscience.472.

The beta adrenergic receptor antagonist propranolol alters mitogenic and apoptotic signaling in late stage breast cancer.

Background: Substantial evidence supports the use of inexpensive β-AR antagonists (beta blockers) against a variety of cancers, and the β-AR antagonist propranolol was recently approved by the European Medicines Agency for the treatment of soft tissue sarcomas. Prospective and retrospective data published by our group and others suggest that non-selective β-AR antagonists are effective at reducing proliferative rates in breast cancers, however the mechanism by which this occurs is largely unknown.

Methods: In this study, we measured changes in tumor proliferation and apoptosis in a late stage breast cancer patient treated with neoadjuvant propranolol.

Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment.

Angiosarcoma is the most common malignant cardiac tumor. Cardiac angiosarcoma is a highly lethal neoplasm that is largely resistant to conventional anti-cancer therapy. Mean survival of patients with cardiac angiosarcoma is only 4 months, and almost all patients will succumb to the disease within 1 year.

5-HT serotonin receptors modulate mitogenic signaling and impact tumor cell viability.

Symptoms of depression are present in over half of all cancer patients, and selective serotonin reuptake inhibitor (SSRI) anti-depressant medications are prescribed to nearly a quarter of these individuals in order to cope with their disease. Previous studies have provided evidence that elevated serotonin (5-HT) and serotonin receptor levels may contribute to oncogenic progression, yet little is known regarding the mechanism by which this occurs. The data demonstrated that serotonin receptor mRNAs and proteins are expressed across diverse cancer types, and that serotonin stimulation of tumor cells activates oncogenic signaling mediators including components of the AKT, CREB, GSK3, and MAPK pathways.

Propranolol and breast cancer-a work in progress.

The non-selective beta-blocker propranolol is a leading candidate for repurposing as a novel anti-cancer agent. Emerging evidence, including human data, suggests that there are multiple mechanisms of action particularly relevant to breast cancer. This editorial reviews a number of recent studies that show it has anti-metastatic activity that warrants clinical investigation, including investigation as a potential perioperative therapy in breast cancer.

Non-selective beta blockers inhibit angiosarcoma cell viability and increase progression free- and overall-survival in patients diagnosed with metastatic angiosarcoma.

Patients with metastatic angiosarcoma undergoing chemotherapy, radiation, and/or surgery experience a median progression free survival of less than 6 months and a median overall survival of less than 12 months. Given the aggressive nature of this cancer, angiosarcoma clinical responses to chemotherapy or targeted therapeutics are generally very poor. Inhibition of beta adrenergic receptor (β-AR) signaling has recently been shown to decrease angiosarcoma tumor cell viability, abrogate tumor growth in mouse models, and decrease proliferation rates in preclinical and clinical settings.

Extracellular matrix composition modulates angiosarcoma cell attachment and proliferation.

Angiosarcoma is a rare and generally fatal tumor composed of aberrant cells of endothelial origin. Because of its infrequency in humans, very little is known about the growth requirements of this vascular sarcoma. Unlike the rapidly proliferating solid tumors from which they are isolated from, many of the established angiosarcoma cell lines exhibit less than robust growth in culture and often fail to form tumors in xenograft models.

Beta-adrenergic receptors are expressed across diverse cancers.

Based largely on retrospective analyses and a handful of prospective case reports, pharmacological inhibition of the beta adrenergic receptors using beta blockers has shown clinical anti-cancer efficacy in reproductive cancers, as well as angiosarcoma and multiple myeloma. Because of the potential promise of beta blockers as an adjunct to standard anti-cancer therapy, it is imperative to identify other tumor types expressing beta adrenergic (β-AR) receptors so future preclinical and clinical studies can be directed at the most promising tumor targets. We performed immunohistochemical detection of β1-AR, β2-AR, and β3-AR across 29 of the most common human cancer types (389 tissues total) and 19 matching non-diseased controls (100 tissues total).

A novel protein expression signature differentiates benign lipomas from well-differentiated liposarcomas.

Benign lipomas and well-differentiated liposarcomas share many histological and molecular features. Due to their similarities, patients with these lipomatous tumors are misdiagnosed up to 40% of the time following radiological detection, up to 17% of the time following histological examination, and in as many as 15% of cases following fluorescent hybridization for chromosomal anomalies. Incorrect classification of these two tumor types leads to increased costs to the patient and delayed accurate diagnoses.

Rho kinase proteins display aberrant upregulation in vascular tumors and contribute to vascular tumor growth.

Background: The serine/threonine protein kinases ROCK1 and 2 are key RhoA-mediated regulators of cell shape and cytoskeletal dynamics. These proteins perform multiple functions in vascular endothelial cell physiology and are attractive targets for cancer therapy based on their roles as oncogenes and metastatic promoters. Given their critical functions in both of these processes, we hypothesized that molecular targeting of ROCK proteins would be exceedingly effective against vascular tumors such as hemangiomas and angiosarcomas, which are neoplasms composed of aberrant endothelial cells.

PD-1 and PD-L1 expression in bone and soft tissue sarcomas.

PD-1 and its ligands have been shown to play a significant role in evasion of malignant tumour cells from the immune system. Last year, the Unites States Food and Drug Administration (FDA) approved anti-PD-1 inhibitors for treatment of non-small cell lung carcinoma and recently expanded the use of immunotherapy for metastatic urothelial cell carcinoma and Hodgkin lymphoma. However, studies on expression of PD-1 and its ligand in malignant bone and soft tissue sarcoma are sparse.

Enhanced expression of Programmed cell death 1 (PD-1) protein in benign vascular anomalies.

Programmed cell death 1 (PD-1) and its ligands have been shown to play a significant role in evasion of malignant tumour cells from the immune system. Last year, the United States Food and Drug Administration (FDA) approved anti-PD-1 inhibitors for treatment of non-small cell lung carcinoma and recently has approved anti-PD-L1 blocker for treatment of metastatic urothelial cell carcinoma. However, the role that the immune system might have on benign tumours including vascular anomalies has received less attention.

Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.

Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation.

Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib.

Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels.

Enrichment of the embryonic stem cell reprogramming factors Oct4, Nanog, Myc, and Sox2 in benign and malignant vascular tumors.

Background: The "stem cell theory of cancer" states that a subpopulation of cells with stem cell-like properties plays a central role in the formation, sustainment, spread, and drug resistant characteristics of malignant tumors. Recent studies have isolated distinct cell populations from infantile hemangiomas that display properties equivalent to aberrant progenitor cells, suggesting that, in addition to malignant tumors, benign tumors may also contain a stem cell-like component.

Methods: In this study, the expression levels of the embryonic stem cell reprogramming factors Oct4, Nanog, Myc, Sox2, and Klf4 were examined via immunohistochemistry in a panel of 71 benign, borderline, and malignant vascular tumors including capillary hemangioma, cavernous hemangioma, granulomatous hemangioma, venous hemangioma, hemangioendothelioma, hemangiopericytoma, and angiosarcoma.

Beta Adrenergic Signaling: A Targetable Regulator of Angiosarcoma and Hemangiosarcoma.

Human angiosarcomas and canine hemangiosarcomas are highly aggressive cancers thought to arise from cells of vascular origin. The pathological features, morphological organization, and clinical behavior of canine hemangiosarcomas are virtually indistinct from those of human angiosarcomas. Overall survival with current standard-of-care approaches remains dismal for both humans and dogs, and each is likely to succumb to their disease within a short duration.

Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade.

Importance: Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major therapeutic advances against this disease have not been reported for decades. Preclinical data indicate that blocking β-adrenergic signaling with propranolol hydrochloride disrupts angiosarcoma cell survival and xenograft angiosarcoma progression.

Activity of 2-aryl-2-(3-indolyl)acetohydroxamates against drug-resistant cancer cells.

Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, and head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multidrug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed.

Functional genomics analysis reveals a MYC signature associated with a poor clinical prognosis in liposarcomas.

Liposarcomas, which are malignant fatty tumors, are the second most common soft-tissue sarcomas. Several histologically defined liposarcoma subtypes exist, yet little is known about the molecular pathology that drives the diversity in these tumors. We used functional genomics to classify a panel of diverse liposarcoma cell lines based on hierarchical clustering of their gene expression profiles, indicating that liposarcoma gene expression profiles and histologic classification are not directly correlated.

Epithelial cell adhesion molecule is expressed in a subset of sarcomas and correlates to the degree of cytological atypia in leiomyosarcomas.

Epithelial cell adhesion molecule (EpCAM) is a protein involved in cell-to-cell attachment and is considered to be strictly expressed in epithelial tissues and epithelial-derived tumors. Furthermore, EpCAM has been shown to be a negative prognostic marker for several carcinomas. In this study, we performed a genomic meta-analysis of gene expression profiles housed in the Cancer Cell Line Encyclopedia to demonstrate that mRNA is expressed at low to moderate levels in certain sarcoma cell lines.

GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is essential for development, wound healing, and tumor progression. The VEGF pathway plays irreplaceable roles during angiogenesis, but how other signals cross-talk with and modulate VEGF cascades is not clearly elucidated. Here, we identified that Gpr126, an endothelial cell-enriched gene, plays an important role in angiogenesis by regulating endothelial cell proliferation, migration, and tube formation.