TY - CHAP
T1 - Tumor microenvironment and nitric oxide
T2 - Concepts and mechanisms
AU - Vedenko, Anastasia
AU - Panara, Kush
AU - Goldstein, Gabriella
AU - Ramasamy, Ranjith
AU - Arora, Himanshu
N1 - Publisher Copyright:
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - The cancer tissue exists not as a single entity, but as a combination of different cellular phenotypes which, taken together, dramatically contribute to the entirety of their ecosystem, collectively termed as the tumor microenvironment (TME). The TME is composed of both immune and nonimmune cell types, stromal components, and vasculature—all of which cooperate to promote cancer progression. Not all immune cells, however, are immune-suppressive; some of them can promote the immune microenvironment to fight the invading and uncontrollably dividing cell populations at the initial stages of tumor growth. Yet, many of these processes and cellular phenotypes fall short, and the immune ecosystem more often than not ends up stabilizing in favor of the “resistant” resident cells that begin clonal expansion and may progress to metastatic forms. Stromal components, making up the extracellular matrix and basement membrane, are also not the most innocuous: CAFs embedded throughout secrete proteases that allow the onset of one of the most invasive processes—angiogenesis—through destruction of the ECM and the basement membrane. Vasculature formation, because of angiogenesis, is the largest invader of the TME and the reason metastasis happens. Vasculature is so sporadic and omnipresent in the TME that most drug therapies are mainly focused on stopping this uncontrollable process. As the tumor continues to grow, different processes are constantly supplying it with the ingredients favorable for tumor progression and eventual metastasis. For example, angiogenesis promotes blood vessel formation that will allow the bona fide escape of tumor cells to take place. Another process like hypoxia will present itself in several forms throughout the tumor (mild or acute, cycling or permanent), starting mechanisms such as epithelial to mesenchymal transitions (EMT) of resident cells and inadvertently placing the cells in such a stressful condition that production of ROS and DNA damage is unavoidable. DNA damage can induce mutagenicity while allowing resistant cells to survive. This is where drugs and treatments can subsequently suffer in effectiveness. Finally, another molecule has just surfaced as being a very important player in the TME: nitric oxide. Often overlooked and equated with ROS and initially assigned in the category of pathogenic molecules, nitric oxide can definitely do some damage by causing metabolic reprogramming and promotion of immunosuppressive phenotypes at low concentrations. However, its actions seem to be extremely dose-dependent, and this issue has become a hot target of current treatment goals. Shockingly, nitric oxide, although omnipresent in the TME, can have a positive effect on targeting the TME broadly. Thus, while the TME is a myriad of cellular phenotypes and a combination of different tumor-promoting processes, each process is interconnected into one whole: the tumor microenvironment.
AB - The cancer tissue exists not as a single entity, but as a combination of different cellular phenotypes which, taken together, dramatically contribute to the entirety of their ecosystem, collectively termed as the tumor microenvironment (TME). The TME is composed of both immune and nonimmune cell types, stromal components, and vasculature—all of which cooperate to promote cancer progression. Not all immune cells, however, are immune-suppressive; some of them can promote the immune microenvironment to fight the invading and uncontrollably dividing cell populations at the initial stages of tumor growth. Yet, many of these processes and cellular phenotypes fall short, and the immune ecosystem more often than not ends up stabilizing in favor of the “resistant” resident cells that begin clonal expansion and may progress to metastatic forms. Stromal components, making up the extracellular matrix and basement membrane, are also not the most innocuous: CAFs embedded throughout secrete proteases that allow the onset of one of the most invasive processes—angiogenesis—through destruction of the ECM and the basement membrane. Vasculature formation, because of angiogenesis, is the largest invader of the TME and the reason metastasis happens. Vasculature is so sporadic and omnipresent in the TME that most drug therapies are mainly focused on stopping this uncontrollable process. As the tumor continues to grow, different processes are constantly supplying it with the ingredients favorable for tumor progression and eventual metastasis. For example, angiogenesis promotes blood vessel formation that will allow the bona fide escape of tumor cells to take place. Another process like hypoxia will present itself in several forms throughout the tumor (mild or acute, cycling or permanent), starting mechanisms such as epithelial to mesenchymal transitions (EMT) of resident cells and inadvertently placing the cells in such a stressful condition that production of ROS and DNA damage is unavoidable. DNA damage can induce mutagenicity while allowing resistant cells to survive. This is where drugs and treatments can subsequently suffer in effectiveness. Finally, another molecule has just surfaced as being a very important player in the TME: nitric oxide. Often overlooked and equated with ROS and initially assigned in the category of pathogenic molecules, nitric oxide can definitely do some damage by causing metabolic reprogramming and promotion of immunosuppressive phenotypes at low concentrations. However, its actions seem to be extremely dose-dependent, and this issue has become a hot target of current treatment goals. Shockingly, nitric oxide, although omnipresent in the TME, can have a positive effect on targeting the TME broadly. Thus, while the TME is a myriad of cellular phenotypes and a combination of different tumor-promoting processes, each process is interconnected into one whole: the tumor microenvironment.
KW - Angiogenesis
KW - Angiogenic switch
KW - Cancer
KW - Cancer metabolism
KW - Cancer-associated fibroblasts (CAFs)
KW - Hypoxia
KW - Immune elimination/equilibrium/escape
KW - Immune surveillance
KW - Immunosuppression
KW - Immunotherapy
KW - Innate and adaptive immunity
KW - Nitric oxide
KW - Sprouting angiogenesis
KW - Stromal cells
KW - Treatment resistance
KW - Tumor microenvironment (TME)
KW - Tumor-associated macrophages (TAMs)
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U2 - 10.1007/978-3-030-50224-9_10
DO - 10.1007/978-3-030-50224-9_10
M3 - Chapter
C2 - 33119871
AN - SCOPUS:85094936053
T3 - Advances in Experimental Medicine and Biology
SP - 143
EP - 158
BT - Advances in Experimental Medicine and Biology
PB - Springer
ER -