The tumor microenvironment: a pitch for multiple players

Abstract

The cancer microenvironment may be conceptually regarded as a pitch where the main players are resident and non-resident cellular components, each covering a defined role and interconnected by a complex network of soluble mediators. The crosstalk between these cells and the tumor cells within this environment crucially determines the fate of tumor progression. Immune cells that infiltrate the tumor bed are transported there by blood circulation and exert a variety of effects, either counteracting or favoring tumor outgrowth. Here, we review and discuss the multiple populations composing the tumor bed, with special focus on immune cells subsets that positively or negatively dictate neoplastic progression. In this scenario, the contribution of cancer stem cells within the tumor microenvironment will also be discussed. Finally, we illustrate recent advances on new integrated approaches to investigate the tumor microenvironment in vitro.

Keywords: NK cells; T lymphocytes; cancer stem cells; dendritic cells; macrophages; myeloid-derived suppressor cells; solid tumors; tumor microenvironment.

Figure 1

Composition of the tumor microenvironment from a mouse melanoma tumor. C57BL/6 mice were injected subcutaneously with 0.75 × 10⁶ B16.F10 melanoma cells. After 14 days tumors were excised and sections stained with the Hematoxylin/Eosin method. (A) 40× Magnification. Blood vessel with red blood cells (red circular cells) is shown. (B) Detail of the blood vessel depicted in (A) with the indication of the various functional structures linking blood vessel and tumor milieu. Yellow arrows, tumor-infiltrating leukocytes; red arrows, red blood cells; black arrows, melanoma cells.

Figure 2

Role of the cancer stem cells in the development of the tumor microenvironment. Cancer progression is generated and sustained by several factors, such as epigenetic forces, somatic mutations, and EMT. On the other hand, these events lead to the generation of distinct cancer stem cell clones inside the cancer moiety, and enrich the cancer stem cell niche. During the late stages of tumor progression these stem cell clones sustain the cancer expansion with their self-renewal ability. Thus, the cancer stem cell niche can also be regarded as a reservoir of self-sustaining cells for the tumor microenvironment.