Thyroid Cancer and Fibroblasts

Thyroid cancer is the most common type of endocrine cancer, and its prevalence continue to rise. Non-metastatic thyroid cancer patients are successfully treated. However, looking for new therapeutic strategies is of great importance for metastatic thyroid cancers that still lead to death. With respect to this, the tumor microenvironment (TME), which plays a key role in tumor progression, should be considered as a new promising therapeutic target to hamper thyroid cancer progression. Indeed, thyroid tumors consist of cancer cells and a heterogeneous and ever-changing niche, represented by the TME, which contributes to establishing most of the features of cancer cells. The TME consists of extracellular matrix (ECM) molecules, soluble factors, metabolites, blood and lymphatic tumor vessels and several stromal cell types that, by interacting with each other and with tumor cells, affect TME remodeling, cancer growth and progression. Among the thyroid TME components, cancer-associated fibroblasts (CAFs) have gained more attention in the last years. Indeed, recent important evidence showed that thyroid CAFs strongly sustain thyroid cancer growth and progression by producing soluble factors and ECM proteins, which, in turn, deeply affect thyroid cancer cell behavior and aggressiveness. Hence, in this article, we describe the thyroid TME, focusing on the desmoplastic stromal reaction, which is a powerful indicator of thyroid cancer progression and an invasive growth pattern. In addition, we discuss the origins and features of the thyroid CAFs, their influence on thyroid cancer growth and progression, their role in remodeling the ECM and their immune-modulating functions. We finally debate therapeutic perspectives targeting CAFs

Generation and Characterization of a Tumor Stromal Microenvironment and Analysis of Its Interplay with Breast Cancer Cells: An In Vitro Model to Study Breast Cancer-Associated Fibroblast Inactivation

Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by α-smooth muscle actin (α-SMA) and cyclooxygenase 2 (COX-2). BCAF aggregates have been identified in the peripheral blood of metastatic BC patients. We generated an in vitro stromal model consisting of human primary BCAFs grown as monolayers or 3D cell aggregates, namely spheroids and reverted BCAFs, obtained from BCAF spheroids reverted to 2D cell adhesion growth after 216 h of 3D culture. We firstly evaluated the state of activation and inflammation and the mesenchymal status of the BCAF monolayers, BCAF spheroids and reverted BCAFs. Then, we analyzed the MCF-7 cell viability and migration following treatment with conditioned media from the different BCAF cultures. After 216 h of 3D culture, the BCAFs acquired an inactivated phenotype, associated with a significant reduction in α-SMA and COX-2 protein expression. The deactivation of the BCAF spheroids at 216 h was further confirmed by the cytostatic effect exerted by their conditioned medium on MCF-7 cells. Interestingly, the reverted BCAFs also retained a less activated phenotype as indicated by α-SMA protein expression reduction. Furthermore, the reverted BCAFs exhibited a reduced pro-tumor phenotype as indicated by the anti-migratory effect exerted by their conditioned medium on MCF-7 cells. The deactivation of BCAFs without drug treatment is possible and leads to a reduced capability of BCAFs to sustain BC progression in vitro. Consequently, this study could be a starting point to develop new therapeutic strategies targeting BCAFs and their interactions with cancer cells

Indications to laparoscopic cholecystectomy

The diffuse ultrasound examination for various abdominal diseases increased in the last decades the diagnosis of asymptomatic gallbladder diseases. High-quality data demonstrate that the majority of patients with asymptomatic gallstones will remain asymptomatic (only 2–4 % will develop symptoms annually) and that the complication rate in asymptomatic patients ranges from 0.3 to 3 % per year. Given the low incidence of symptoms development and complication rate per year in nontreated patients, prophylactic laparoscopic cholecystectomy is currently not recommended as standard treatment. N evertheless, according to the conclusion of 2009 Cochrane Review on LC in silent stones, there is no RCT or high-level studies which offer scientifi c evidence to refuse LC to asymptomatic gallbladder stone patients. There is no evidence to recommend prophylactic LC in asymptomatic gallbladder stone patients neither for diabetics, patients on long-term somatostatin, nor patients with porcelain gallbladder in Western countries. Also in patients with gallbladder stones >3 cm, there is not enough data available to recommend prophylactic LC to prevent gallbladder cancer. Nevertheless, recent data suggest that selective prophylactic LC is advisable in some subgroup of patients. Microcalculi and bile sludge in conjunction with a functioning gallbladder are more likely to predispose patients to calculi migration and subsequent onset of choledocholithiasis and acute pancreatitis. Incidental diagnosis of cholelithiasis in preoperative or intraoperative setting for other medical conditions can be treated laparoscopically in the same session if it does not add any risk of conversion and no prosthetic material is being used. A s the risk of sickling, in patients suffering from sickle cell anemia, is reduced by a laparoscopic approach, it should be the fi rst choice. Some ethnic groups and inhabitants of certain geographical areas are more likely to develop gallbladder cancer. Also specifi c ultrasound fi ndings, like selective mucosal calcifi cations, increase the risk of gallbladder cancer. These patients could benefi t from prophylactic LC. C ardiac-transplanted patients with asymptomatic cholelithiasis should undergo LC

Surgical management of acutely presenting gastrointestinal stromal tumors of the stomach among elderly: experience of an emergency surgery department

Introduction: The incidence of gastrointestinal stromal tumors (GISTs), requiring often an emergency surgical management, is extremely rare among elderly. We aimed to present the experience of the Emergency Surgery Department, Brotzu Hospital, in the management of elderly patients with GIST related emergencies.Methods: This study was carried out on 12 patients with gastrointestinal stromal tumors who presented to in an emergency situation during the period from January 2010 to December 2013. All patients' data, clinical presentations, surgical procedures, complications, and survival data were collected and analyzed.Results: Between 2010 and 2013, 12 patients (8 males and 4 females), with a mean age of 70 years (range: 65-79 years) were admitted with different emergency presentations of clinically and radiologically suspected GISTs. The incidence of proximal obstruction was 41.7% of all gastric GIST cases, resulting acute gastrointestinal bleeding and perforation in 41.7% and 16.6% respectively. The mean length of hospitalization was 9.1 +/- 2.3 days and there were no posterative complications or mortalities. At a mean follow-up of 21 months, 11 patients (91.6%) were alive and disease free.Discussions: Although GISTs are uncommon among elderly, their incidence is increasing especially in their emergency presentation and surgeon should be prepared to treat this condition following the principles of GIST surgery as stated by the GIST consensus conference.Conclusions: In conclusion our data demonstrate that age itself does not affect the outcome of surgical treatment of GISTs in emergency situation. (C) 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively

Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation

Myofibroblasts are activated fibroblasts involved in tissue repair and cancer. They are characterized by de novo expression of α-smooth muscle actin (α-SMA), immunoregulatory phenotype and paracrine interaction with normal and tumorigenic cells leading to cell proliferation. At the end of wound-healing myofibroblasts undergo apoptotic cell death, whereas in vitro-activated fibroblasts are also subjected to a programmed necrosis-like cell death, termed nemosis, associated with cyclooxygenase-2 (COX-2) expression induction and inflammatory response. Furthermore, myofibroblasts form clusters during wound healing, fibrotic states and tumorigenesis. In this study, we generated and analysed clusters such as spheroids from human primary cutaneous myofibroblasts, which represent a part of stromal microenvironment better than established cell lines. Therefore, we evaluated apoptotic or necrotic cell death, inflammation and activation markers during myofibroblasts clustering. The spheroids formation did not trigger apoptosis, necrotic cell death and COX-2 protein induction. The significant decrease of α-SMA in protein extracts of spheroids, the cytostatic effect exerted by spheroids conditioned medium on both normal and cancer cell lines and the absence of proliferation marker Ki-67 after 72 h of three-dimensional culture indicated that myofibroblasts have undergone a deactivation process within spheroids. The cells of spheroids reverted to adhesion growth preserved their proliferation capability and can re-acquire a myofibroblastic phenotype. Moreover, the spontaneous formation of clusters on plastic and glass substrates suggests that aggregates formation could be a physiological feature of cutaneous myofibroblasts. This study represents an experimental model to analyse myofibroblasts deactivation and suggests that fibroblast clusters could be a cell reservoir regulating tissues turnover