**7. Cancer stem cells (CSC); exosomes**

Malignant tumors arise from a small subset of cancer cells, have tumor heterogeneity, and small populations of cells with characteristics equivalent to SCs. These cells, called cancer stem cells (CSC) or cancer-initiating cells (CIC), have been identified in many malignancies and are thought to form the tumor clonogenic nucleus. The CSCs share many characteristics of ES and show activation of one or more signal transduction pathways, which are involved in tissue homeostasis and development, including Notch, Hedgehog (Hh), and Wnt pathways. Notch signaling, similar to the Wnt and Hh pathways, is a pathway for determining the fate of the evolutionarily conserved primordial cell, with great relevance in the biology of cancer, from CSC to angiogenesis and tumor immunity. The CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiation therapy. The new treatment strategies seek to control the replication, survival, and differentiation of the CSCs [70]. These cells originate from a more differentiated cancer cell, with self-renewing properties, probably as a result of epithelial to mesenchymal transmission [71].

angiogenesis, and tumor metastasis, and the mechanism of interaction between the cancer cells and the tumor cells involves the exchange of biological material through exosomes. On the other hand, exosomes induce the formation of the premetastatic niche, which regulates tumor metastasis. Mechanisms mediated by exosomes contribute to resistance to antitumor therapy. Certain exosomes have an influence on tumors to evade immune surveillance [75]. Exosomes derived from SCs provide information related to the regulation of genes to target cells, for cell growth and angiogenesis by the modulation of various signaling pathways. Exosomes derived from MSCs potentiate the expression of VEGF in tumor cells by activating the kinase 1/2 pathway regulated by extracellular signal regulated kinases (ERK1/2) that

Therapeutic Strategies of Secretome of Mesenchymal Stem Cell

http://dx.doi.org/10.5772/intechopen.78092

199

The ExMVs released by adipose mesenchymal stem cells (ASC) may contribute to angiogenesis induced by ASCs. In CSC, exosomes derived only from CD105+ CSCs conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation. A specific source of the ExMVs derived from CSCs contributes to triggering the angiogenic process and metastatic diffusion during tumor progression. The effects of exosomes of different types of SCs on angiogenesis are similar to those of exosomes derived

Exosomes released from SCs contribute to tumor metastasis. Several key steps in tumor invasion and metastasis are associated with MSCs, and include the epithelial-mesenchymal transition and the induction of SC-like properties that allow CSCs to increase their survival capacity

Recently, CSCs have been used in the diagnosis and treatment of cancer. The exosomes released from prostate and breast cancers have specific biomolecular characteristics, including the expression of several exosomal markers such as CD9, CD63, CD81, ALIX, and TSG101. In addition, the exosomes derived from GC-MSC contain miR-221, which is a new biomarker for the diagnosis of several tumors. The finding of tumor biomarkers is a new diagnostic tool. The release of exosome cells provides valuable detailed molecular information about the cell of origin and the tumor characteristics, can be isolated from easily accessible body fluids, and

can provide specific information for the predictive diagnosis of multiple tumors [79].

Due to its complexity, the research and application of cell therapy with cells and cellular products should be considered with a multidisciplinary and translational approach and represents a great therapeutic potential for refractory diseases to conventional treatments such as noncommunicable chronic diseases: diabetes, cardiovascular ischemic diseases, cerebrovascular or renal diseases, degenerative diseases such as cancer, neurodegenerative such as

Thus, cell therapy with MSCs emerges as a promising therapeutic tool, the main therapeutic objective of which is healing through trans-differentiation to repair and replace

promote tumor growth [76].

from SCs in tumor growth [77].

**8. Future conclusions and addresses**

Alzheimer's disease, multiple sclerosis, and aging.

through circulation [78].

The most important and useful property of the CSC is that of self-renewal and characteristic differentiation, which is considered as a one-way specialization process as the cells develop the functions of their final destination and lose their immature characteristics, such as selfrenewal. This property shows parallels between SCs and cancer cells. The tumors originate by the transformation of normal SCs by means of similar signaling routes, to which they regulate self-renewal, both of SCs and CSCs; the latter include the undefined potential of self-renewal that starts tumorigenesis. Otherwise, CSCs could be derived from a SC of normal tissue that undergoes a transformation as a result of oncogenic somatic mutations, due to the influence of extrinsic microenvironmental factors [72].

The CSCs are associated with tumor onset, metastasis, progression, invasion, recurrence, and resistance to therapies, and they play a central role in the biology of cancer cells; they interact with their surrounding cells inducing angiogenesis and metastasis. In the tumor microenvironment, multiple types of cells coexist, including adult SCs, CSCs, and stromal cells, and communicate with each other in modulating, tumor progression, functionally release exosomes that can be absorbed by CSCs or adult SCs, and modify their phenotype. Recent studies show that exosomes participate in interactions between cells within the tumor microenvironment by means of exosomal signals, modulating tumor progression [73].

We take Hannafon's approach in questions related to the function of the exosomes involved in the interaction of CSCs, adult SCs, and the surrounding cells within the tumor microenvironment, which are:

Do CSCs or adult SCs secrete exosomes that affect the function of the stromal cell? Are CSCs or adult SCs modified by the exosomes released from CSCs and surrounding stromal cells?

What are the possible molecular mechanisms and the biological consequences of exosomemediated interactions between CSCs, adult SCs, and the cells that surround them? [74].

The SCs secrete a large number of exosomes, and in the extracellular environment, they function as intercommunicators in the tumor microenvironment and actively in tumorigenesis, angiogenesis, and tumor metastasis, and the mechanism of interaction between the cancer cells and the tumor cells involves the exchange of biological material through exosomes. On the other hand, exosomes induce the formation of the premetastatic niche, which regulates tumor metastasis. Mechanisms mediated by exosomes contribute to resistance to antitumor therapy. Certain exosomes have an influence on tumors to evade immune surveillance [75].

Exosomes derived from SCs provide information related to the regulation of genes to target cells, for cell growth and angiogenesis by the modulation of various signaling pathways. Exosomes derived from MSCs potentiate the expression of VEGF in tumor cells by activating the kinase 1/2 pathway regulated by extracellular signal regulated kinases (ERK1/2) that promote tumor growth [76].

The ExMVs released by adipose mesenchymal stem cells (ASC) may contribute to angiogenesis induced by ASCs. In CSC, exosomes derived only from CD105+ CSCs conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation. A specific source of the ExMVs derived from CSCs contributes to triggering the angiogenic process and metastatic diffusion during tumor progression. The effects of exosomes of different types of SCs on angiogenesis are similar to those of exosomes derived from SCs in tumor growth [77].

Exosomes released from SCs contribute to tumor metastasis. Several key steps in tumor invasion and metastasis are associated with MSCs, and include the epithelial-mesenchymal transition and the induction of SC-like properties that allow CSCs to increase their survival capacity through circulation [78].

Recently, CSCs have been used in the diagnosis and treatment of cancer. The exosomes released from prostate and breast cancers have specific biomolecular characteristics, including the expression of several exosomal markers such as CD9, CD63, CD81, ALIX, and TSG101. In addition, the exosomes derived from GC-MSC contain miR-221, which is a new biomarker for the diagnosis of several tumors. The finding of tumor biomarkers is a new diagnostic tool. The release of exosome cells provides valuable detailed molecular information about the cell of origin and the tumor characteristics, can be isolated from easily accessible body fluids, and can provide specific information for the predictive diagnosis of multiple tumors [79].
