Targeting Tumor Microenvironment for Cancer Therapy

Abstract

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, "tumor on a chip" or multicellular tumor-spheroids.

Keywords: Tumor microenvironment; cancer therapy; models for tumor microenvironment study; nanomedicines; tumor development.

Figure 1

Anatomy of the tumor microenvironment (TME). (A) The TME of a late stage solid tumor is highly heterogeneous and complex. (B) Exosomes play important roles in paracrine and autocrine communication between TME cells, being preponderant in the modulation and development of the tumor. Exosomes are also involved in the transformation of normal cells adjacent to the TME into tumor cells. The extracellular matrix (ECM) in the TME is frequently dense and stiff, resulting in desmoplasia. (C) The rapid growth of tumor cells results in hypoxic regions and lack of nutrients within the tumor, causing the Warburg effect. This metabolic shift into anaerobic glycolytic pathway results in acidification of the TME. (D) The rapid growth of tumor cells induces angiogenesis and consequent formation of chaotic branching structures. Stromal cells (including Cancer-associated fibroblasts and mesenchymal stromal cells) and cells from the immune system (both lymphoid and myeloid lineage cells) are important players in tumor development and prognosis.

Figure 2

Strategies used to target tumor microenvironment for cancer therapy.

Figure 3

A single nanomaterial (e.g., nanoparticles) can be functionalized with different moieties to target different cell populations in the TME (tumor and stromal cells), enabling a combined strategy for cancer therapeutics. CAFs, Cancer-associated fibroblasts; FRβ, folate-receptor beta; PI-88, Phosphomanno-pentose sulfate.

Figure 4

Main properties of in vitro 2D and 3D culture systems [187,188]. CAF, Cancer-associated fibroblast; ECM, Extracellular matrix.