Transfer of malignant traits as opposed to migration of cells: A novel concept to explain metastatic disease

Abstract Metastatic disease is believed to develop following dissemination of cells to target organs. Inability of this theory to effectively explain certain phenomena such as patterns of metastatic spread, late metastasis formation, different gene patterns between primary cancer and metastasis have brought forward the need for alternative models. Recent discoveries have strengthened the validity of theories supporting a humoral transfer of malignant traits as opposed to migration of malignant cells to explain metastatic disease in cancer patients. In light of this new evidence, we would like to highlight a model that offers a new perspective to explain cancer metastasis. In the system that we theorize, genetic material released by cancer cells would travel, either free or packed in exosomes, through the blood. Target cells located in organs deriving from the same embryological layer might uptake this genetic material due to expression of specific receptors. Interplay with the immune system would determine the fate of these oncofactors and would regulate their ability to circulate in the blood, integrate in the genome and be transcribed. We also hypothesize that the expression of cell membrane receptors such as integrins, to which cancer exosomes ligate might be mediated by inherited or acquired oncosuppressor mutations

Kommerell’s diverticulum and aneurysmal right-sided aortic arch: A case report and review of the literature

AbstractRight-sided aortic arch is a rare variant of the thoracic vascular anatomy that may be accompanied by an aberrant origin of the left subclavian artery. We report a true aneurysm of the distal arch and descending thoracic aorta in a patient with right-sided arch and review previous descriptions of aneurysms of anomalous right-sided aortas. In our patient, the left subclavian artery originated at the junction between the distal arch and the descending thoracic aorta located in the right chest and was aneurysmal (Kommerell’s diverticulum); the thoracic aorta was also aneurysmal. Extra-anatomic left subclavian-to-carotid transposition was performed before the intrathoracic procedure. Subsequently, a right thoracotomy provided adequate exposure for repairing the aortic aneurysm and oversewing the aneurysmal origin of the subclavian artery. Because the distal aortic arch was involved, deep hypothermia and circulatory arrest were used. Only five previous instances of true aneurysms of a right-sided aortic arch have been reported; four of these patients underwent operative repair (via bilateral thoracotomy, median sternotomy, or right thoracotomy). We believe that a right thoracotomy provides good exposure and avoids the morbidity associated with bilateral thoracotomy. The reconstruction of the subclavian artery has not previously been reported in this setting. Performing subclavian reconstruction as an extrathoracic procedure before the intrathoracic repair would be expected to reduce the subsequent risk of distal ischemia or subclavian steal without increasing the overall morbidity associated with the procedure. (J Vasc Surg 2000;32:1208-14.

Staged hepatectomy for bilobar colorectal hepatic metastases

AbstractObjectivesThis study describes the management of patients with bilobar colorectal liver metastases (CRLM).MethodsA retrospective collection of data on all patients with CRLM who were considered for staged resection (n= 85) from January 2003 to January 2011 was performed. Patients who underwent one hepatic resection were considered to have had a failed staged resection (FSR), whereas those who underwent a second or third hepatic resection to produce a cure were considered to have had a successful staged resection (SSR). Survival was calculated from the date of diagnosis of liver metastases. Complete follow-up and dates of death were obtained from the Government of Quebec population database.ResultsMedian survival was 46months (range: 30–62months) in the SSR group and 22months (range: 19–29months) in the FSR group. Rates of 5-year survival were 42% and 4% in the SSR and FSR groups, respectively. Fifteen of the 19 patients who remained alive at the last follow-up date belonged to the SSR group.ConclusionsIn patients in whom staged resection for bilobar CRLM is feasible, surgery would appear to offer benefit

Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum

Extracellular vesicles (EVs) are mediators of intercellular communication under bothhealthy and pathological conditions, including the induction of pro-metastatic traits,but it is not yet known how and where functional cargoes of EVs are delivered to theirtargets in host cell compartments. We have described that after endocytosis, EVsreach Rab+late endosomes and a fraction of these enter the nucleoplasmic reticu-lum and transport EV biomaterials to the host cell nucleoplasm. Their entry thereinand docking to outer nuclear membrane occur through a tripartite complex formedby the proteins VAP-A, ORP and Rab (VOR complex). Here, we report that theantifungal compound itraconazole (ICZ), but not its main metabolite hydroxy-ICZor ketoconazole, disrupts the binding of Rab to ORP–VAP-A complexes, leadingto inhibition of EV-mediated pro-metastatic morphological changes including cellmigration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhi-bition of the VOR complex was maintained, although the ICZ moieties responsiblefor antifungal activity and interference with intracellular cholesterol distributionwere removed. Knowing that cancer cells hijack their microenvironment and thatEVs derived from them determine the pre-metastatic niche, small-sized inhibitors ofnuclear transfer of EV cargo into host cells could nd cancer therapeutic applications,particularly in combination with direct targeting of cancer cell

Novel blood test to predict neoplastic activity in healthy patients and metastatic recurrence after primary tumor resection

We reported that single oncosuppressor-mutated (SOM) cells turn malignant when exposed to cancer patients’ sera. We tested the possibility to incorporate this discovery into a biological platform able to detect cancer in healthy individuals and to predict metastases after tumor resection. Blood was drawn prior to tumor resection and within a year after surgery. Blood samples from healthy individuals or metastatic patients were used as negative and positive controls, respectively. Patients at risk for cancer were included in the screening cohort. Once treated, cells were injected into nonobese diabetic/severe combined immunodeficiency mice to monitor tumor growth. All samples of sera coming from metastatic patients transformed SOM cells into malignant cells. Four samples from screened patients transformed SOM cells. Further clinical tests done on these patients showed the presence of early cancerous lesions despite normal tumor markers. Based on the xenotransplants size, we were able to predict metastasis in three patients before diagnostic tests confirmed the presence of the metastatic lesions. These data show that this serum-based platform has potentials to be used for cancer screening and for identification of patients at risks to develop metastases regardless of the Tumor Node Metastasis (TNM) stage or tumor markers level

Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment

<div><p>The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity <i>in vitro</i> and <i>in vivo</i>. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells.</p></div

Adult colo-colonic intussusception caused by congenital bands: A case report and literature review

Introduction: Intussusception refers to the telescoping of a segment of bowel into the lumen of an adjacent segment. While pediatric intussusception is common and generally idiopathic, adult intussusception is exceedingly rare and is usually attributable to a pathologic lead point. Presentation of case: 37-year-old man who presented with abdominal pain, and was preoperatively diagnosed with a colo-colonic intussusception. Intraoperatively, the lead point was found to be congenital bands, and there was no evidence of underlying malignancy. He underwent a laparoscopic-assisted extended right hemicolectomy with side-to-side ileo-colic anastomosis. Discussion: Colo-colonic intussusception is a rare cause of intestinal obstruction in adults. Patients generally present with subacute abdominal pain and obstructive symptoms, rendering the clinical diagnosis challenging. Computed tomography has been shown to be the most accurate diagnostic imaging modality. Due to the high incidence of underlying malignancy in adult colo-colonic intussusception, en-bloc resection of the involved bowel segment remains the standard of care. Conclusion: Congenital bands can serve as a lead point in colo-colonic intussusception, particularly in younger adults. Prompt surgical intervention remains paramount to limit morbidity

hESCs-Exo decreased cancer cell proliferation and increased cancer cell death.

<p>MDA-MB231 and HT29 cells were cultured for 3 days in control medium (5%FBS), or with exosomes derived from fibroblast-CM (Fibro-Exo) or hESCs-CM (hESCs-Exo), and cells were analyzed for their growth potential (A-E), and apoptosis (F). (A) Bright field pictures of cell cultures at 3 days post-treatments. Note the significant dose-dependent reduction in cell density in cultures maintained in hESCs-Exo. Scale bar: 50 μm. (B and C) note that the legend is the same for all graphs: (B) 100,000 cells were plated and their number was counted after 2 and 3 days of culture. Values are presented as mean ± SD (n = 3 independent cultures, *P < 0.05, **P < 0.01, ***P < 0.001). (C) The metabolic activity following treatment for 2 and 3 days. Cultures were incubated for 5 h with Alamar Blue and data acquired by spectrofluorometry. Data are presented as mean ± SD and are representative of 3 independent experiments (*P < 0.05, **P < 0.01, ***P < 0.001). (D and E) CFSE load dilution in cultures at 3 days post-treatments. Full refer to CFSE loading at the beginning of the culture period. Numbers in brackets are the percentages of fully CFSE-loaded cells (cells that did not divide yet). Data are mean ± SD (n = 3 independent experiments, *P < 0.05, **P < 0.01, ***P < 0.001). (F) Cell apoptosis analyses following labeling with Annexin V and loading of propidium iodide (PI). Apoptotic cells (Annexin V positive and PI negative) were scored and their percentages were shown (n = 3 independent cultures, **P < 0.01, ***P < 0.001).</p