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.

Cancer Stem Cells, Together with Mesenchymal Stem Cells and Other Cooperative Cells, Govern the Initiation and Development of Cancer

“…The group of cells of the center illustrates the general structure of a cancer niche that includes many types of cells distinguished here by the color of their nucleus: green for CSCs, orange for MSCs, red for normal cancer cells, blue for examples on non-cancer cells, such as immune cells, that participate in cancer function. The dots spread below the cells are the two types of EVs secreted by all cells of the group: the small exosomes released upon exocytosis of the multi-vesicular bodies, the endocytic vacuoles that contain them; the larger ectosomes assembled at mini-rafts of the plasma membranes and then released by shedding of cell surface mini-expansions [5,10]. Various factors (interleukins, cytokines, growth factors, not shown) are secreted by all these cells.…”

“…CSCs, identified a few years after 2000, account for significant fractions of the cells concentrated within cancer niches together with normal cancer cells, MSCs and various other collaborative, non-cancer cells, that participate in cancer functions (Figure 1). Functionally, however, the critical properties of CSCs are original [10][11][12][13]16,28,29]. Shared with MSCs can be other properties, such as broad proliferation capacity, signaling and expression of stem cell markers.…”

“…Subpopulations of heterogeneous CSC revealed their capacity of self-renewal and aberrant differentiation for divergent lineages of cancer cells [6][7][8]. CSC concentrations were found to occur within small tissue volumes, the niches, analogous to the stromas of non-cancer cells [9,10]. Niches are the sites of high degree CSC plasticity dependent on transitions from slowly cycling quiescent phases to actively proliferative phenotypes [10][11][12].…”

“…CSC concentrations were found to occur within small tissue volumes, the niches, analogous to the stromas of non-cancer cells [9,10]. Niches are the sites of high degree CSC plasticity dependent on transitions from slowly cycling quiescent phases to actively proliferative phenotypes [10][11][12]. Within niches, stem cells and their EVs are accompanied by other cells and their EVs: normal cancer cells, fibroblasts, immune (macrophages, lymphocytes) and other cells, all cooperative to cancer function (Figure 1) [12][13][14][15][16][17][18].…”

“…The tumor microenvironment (TME), different from the non-cancer microenvironments, includes in space the niches and other areas of cancer development and growth [19,20]. Finally, studies about CSCs and their associated cells/structures have been developed in areas of potential interest for therapeutic development [10]. Some of these studies have already reached the field of clinical medicine [21,22].…”