Long Term Effects of Radiation and Combined Modalities on Mouse Lung

The lung appears to be the major dose-limiting organ in radiation of the thorax. Early responses (\u3c1 week) involve the type II pneumocyte and increased surfactant biosynthesis and secretion. Later changes, which appear to be related to the surfactant response, lead to classical radiation pneumonitis, which is often fatal. Animals which survive radiation pneumonitis develop progressive fibrosis, a late-appearing response, which reduces compliance and available air space, and is usually fatal. This study centers on the fine structural changes in the lungs of LAF1 mice, 63 weeks following various radiation exposures (5-13 Gy). Doses which are subthreshold in evoking surfactant and pneumonitic responses precipitate fibrosis and atelectasis by 63 weeks, and involve type II pneumocyte sloughing and degeneration. Of the two major deterrents to lung irradiation (pneumonitis and fibrosis), these results suggest that fibrosis always follows pneumonitis, but pneumonitis is not a necessary preliminary step to fibrosis. Bleomycin elicits several morphological alterations characteristic of radiation, and, when combined with the latter, appears to exacerbate radiation effects

7099SHI

Abstract. Background: 4-1BB (CD137) is a member of the tumor necrosis factor receptor superfamily. It interacts wit

Tumor Vasculature: a Target for Anticancer Therapies

Historically, approaches to improve cancer therapy have focused primarily on achieving increased tumor cell kill. Recently however another treatment approach has garnered considerable attention. Rather than targeting the neoplastic cell population directly, this strategy endeavors to impair the tumor’s nutritiona

Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specific 6 (Gas6) protein are expressed by a number of host cells. The Gas6/Axl signaling pathway has been implicated in the promotion of tumor cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. As a result, Axl is an attractive, novel therapeutic target to impair multiple stages of tumor progression from both neoplastic and host cell axes. This review focuses on the role of the Gas6/Axl signaling pathway in promoting the immunosuppressive tumor microenvironment, as immune evasion is considered one of the hallmarks of cancer. The review discusses the structure and activation of the Gas6/Axl signaling pathway, GAS6 and AXL expression patterns in the tumor microenvironment, mechanisms of Axl-mediated tumor immune response, and the role of Gas6/Axl signaling in immune cell recruitment

Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer

Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically

The Role of Cathepsins in the Growth of Primary and Secondary Neoplasia in the Bone

The upregulation of proteolytic enzymes has been demonstrated to promote primary tumor development and metastatic bone cancer. The secreted proteases increase tumor growth and angiogenesis, and potentiate neoplastic cell dissemination. This article reviews the role and mechanisms of cathepsins in normal physiology, cancer, bone remodeling, and the tumor–bone interface, with a specific focus on cathepsins B, D, H, G, L, and K. In this review, we highlight the role of cathepsins in primary bone cancer (i.e., osteosarcoma (OS)), as well as metastatic breast (BCa) and prostate (PCa) cancer. In addition, we discuss the clinical utility and therapeutic potential of cathepsin-targeted treatments in primary and secondary bone cancers

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micro-metastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesis in vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients.Fil: Sudhan, Dhivya R.. University of Florida; Estados UnidosFil: Rabaglino, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Wood, Charles E.. University of Florida; Estados UnidosFil: Siemann, Dietmar W.. University of Florida; Estados Unido

E-cadherin plasticity in prostate cancer stem cell invasion

Prostate cancer that has progressed to metastatic disease remains largely untreatable. Nearly 90% of patients with advanced prostate cancer develop skeletal metastases, resulting in a substantial reduction in the quality of life and a drastic worsening of patient prognosis. The mechanisms involved in prostate cancer cell dissemination, however, remain poorly understood. We previously reported the identification of a highly tumorigenic E-cadherin positive prostate tumor stem cell subpopulation that expressed the embryonic stem cell markers SOX2 and OCT3/4. We herein demonstrate that this subpopulation is also highly invasive and, importantly, is capable of altering its E-cadherin expression during the process of invasion. The non-tumorigenic E-cadherin negative subpopulation which minimally expresses SOX2 or OCT3/4 was found to be poorly invasive. In addition, targeted knockdown of SOX2 or OCT3/4 markedly suppressed the invasion of prostate cancer cells. Taken together, these findings indicate that the expression of SOX2 or OCT3/4 is required for invasive cell capacity, but the ability to modulate E-cadherin is the key permissive factor enabling cancer stem cell invasion in vitro. We therefore propose a model in which the post-epithelial to mesenchymal transition phenotype progresses to a frank, aggressive, and invasive phenotype by a process requiring the acquisition of E-cadherin plasticity. Considering the clinical significance of the metastatic complications of prostate adenocarcinoma, the identification of factors that promote the dissemination of the malignant prostate phenotype is essential to establish effective therapies to combat this disease in future