Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

Abstract

Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases.

Keywords: cancer differentiation; cancer progression and relapse; cancer stem cells; clinical medicine; extracellular vesicles; mesenchymal stem cells; metastasis; niches; non-stem cancer cells; normal; therapy; tumoral microenvironment.

Figure 1

Various types of cells and their secreted vesicles that are present and active at cancer niches. At the top, two stem cells of a large size are shown attached to each other. Both the green cancer stem cells (CSC, left) and the orange mesenchymal stem cells (MSC, right) illustrate the secretion of two types of extracellular vesicles (EVs): small exosomes (light blue dots), diffusing out upon the exocytosis of their intracellular containers, the endocytic vacuoles multivesicular bodies (MVBs), and large ectosomes (membranes around yellow lumena), released by shedding of surface mini expansions. EV secretion occurs not only from the large-size cell images, but also from small cells distributed at the bottom, where, however, secretion is not shown. Secreted EVs navigate in the space among the cells. In the lower group, the cells with green and orange nuclei are CSCs and MSCs; cells with red nuclei are normal cancer cells; and cells with blue nuclei are non-cancer cells, for example immune cells that participate in cancer functions. Among their active functions, EVs mediate various types of paracrine and autocrine fusions, which are established with target cells of and outside the niches. Analogously, released fluid agents (interleukins, cytokines, growth factors) and metabolites move in all directions in the space, as suggested by the arrows. The red vessel to the right documents the process of angiogenesis, the generation of new vessels in the depth of cancers. The key role of CSCs in many processes governing cancer life depends also on their cooperation and signal exchange with the other cell types distributed within the niches.

Figure 2

Drawing of a tumor microenvironment (TME) with reference to various types of cells, their processes, and their functions. The extracellular matrix (ECM) documents properties of the cancer environment, which is important for direct interaction with the cells. The apparent connection between the images close to the external line and their names, permits one to distinguish the nature of the present cells. The two stem cells, cancer (CSC, light blue) and mesenchymal (MSC, green), are located at the top and top right. Among the other cells, normal cancer cells, which are highly abundant in their masses (not shown), are known to differ considerably from CSCs. Fibroblasts, macrophages, and lymphocytes are filtered cells that contribute to the TME activity by their cooperation in cancer-protective and cancer-associated processes. All cells produce, by secretion, their extracellular vesicles (EVs). The highly functional and molecular relevance of the vesicles from the two stem cells are suggested by the close location of their EV to the name of their cell of origin. Cells mentioned so far, labeled by the same colors, are present also in the central area of the image. The dots at the surface of the cells are EVs in continuity, possibly involved in release or fusion, which are the processes of molecular transfer between cells. The terms angiogenesis and circadian clock do not describe single cells, but instead are complex processes taking place in TMEs. They require the cooperation of CSCs with various cooperating cells.