A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Abstract

Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

Structural and Ultrastructural Analysis of the Multiple Myeloma Cell Niche and a Patient-Specific Model of Plasma Cell Dysfunction

“…This is expected due to the high percentage of monoclonal cells present within BM from which the constructs were originally derived and the relatively simple type I collagen hydrogels in which they were seeded. These high myeloma constructs indicated the importance of the in vivo tumor microniche for the in vitro study of long-lived plasma cells because without these essential components or additional factors introduced, plasma cells are unable to survive for 5 days in vitro (Cassese et al, 2003; Arce et al, 2004; Cretu & Brooks, 2007; Schwendener & Mete, 2014).…”

“…Previous studies have demonstrated that in order to maintain their phenotype in culture, PCs require components of the tumor microenvironment such as survival factors and/or BM stromal cells (Cassese et al, 2003; Wardemann et al, 2004; Cretu & Brooks, 2007; Wols et al, 2014). These reports have also indicated the importance of IL-6 for the maintenance of plasma cells in vitro as well as playing a key role in the pathogenesis in myeloma cells (Scheller et al, 2011; Schwendener & Mete, 2014). Thus, new models are necessary to investigate the molecular mechanisms that regulate PC homeostasis.…”

ETV1 inhibition depressed M2 polarization of tumor-associated macrophage and cell process in gastrointestinal stromal tumor via down-regulating PDE3A

“…(15,16) Tumor associated macrophages (TAM) is a major component of the inflammatory cells those infiltrate in the tumor microenvironment, derived from the white blood cells from bone marrow and evolved from peripheral blood monocytes. (17) Studies have shown that there are two polarization types of TAM in different environmental conditions, i.e., M1 and M2. (18) Among them, M2 polarization inhibits the anti-tumor immune response and releases various factors, to directly or indirectly promote tumor angiogenesis, tumor growth and tumor metastasis.…”