1. Tumor microenvironment (TME)
The tumor microenvironment (TME) provides a secure environment for
cancer cells to evade the desired outcomes of various treatments.
Essentially, the TME is a complex and dynamic ecosystem composed of
diverse factors that play crucial roles in inhibiting apoptosis,
proliferation, migration, immune evasion, treatment resistance,
metastasis, metabolic reprogramming, and all stages of tumorigenesis
[5]. The tumor microenvironment factors are generally divided into
two main components: cellular components (such as tumor-associated
macrophages (TAMs), tumor-infiltrating lymphocytes (TILs),
myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts
(CAFs), and endothelial cells (ECs) which all of them are stromal
cells), and non-cellular components (such as growth factors, various
chemokines and cytokines, interstitial fluids, metabolites,
extracellular matrix (ECM) and exosomes) [5, 6]. Therefore,
targeting the TME is a potentially effective strategy for achieving
fruitful outcomes of cancer therapy, and small molecules can easily
penetrate the TME and ultimately reach tumor cells and affect them
[6]. The tumor microenvironment is a hypoxic and low-pH environment
[6]. The rapid growth of tumor cells causes hypoxia, which
subsequently causes the release of stimulating factors such as vascular
endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and
hypoxia-inducible factor-1α (HIF- 1α) [5]. Also, the condition of
hypoxia in TME affects the endothelial cells by secreting angiogenic
factors from the tumor and subsequently promoting angiogenesis [7,
8]. In the TME, the most abundant stromal cells are cancer-associated
fibroblasts (CAFs) that can produce abnormal extracellular matrix (ECM)
which supports tumor cell migration [9]. TME reshaping creates the
conditions for tumor cells to interact with surrounding fibroblasts,
immune cells, and endothelial cells, leading to the induction of a
variety of biological events, including angiogenesis, migration,
proliferation, immune system suppression, and drug resistance, which
ultimately causes tumor growth [9-18].
One of the important events in the TME is cell interaction and cell
communication with the ECM because this interaction causes the release
of factors that play a role in ECM remodeling and immune evasion, which
ultimately strengthens treatment resistance [19]. Other important
events are the generation of exosomes by benign and malignant cells,
TME-specific metabolic patterns, and circulating deregulated microRNAs
that increase treatment resistance [19]. There are many different
types of immune cells in the TME that block the immune response, in
addition, around the tumor cells, there are a set of inflammatory
molecules that cause the failure to identify and eliminate cancer cells
by the immune system, which together make TME a complex and
heterogeneous space and they often cause an uncontrollable process in
the growth and development of tumors [5, 20-24]. On the whole, a
wide range of events and factors from biochemical agents, and a hypoxic
environment to abnormal mechanical forces cause treatment resistance
[19]. In the following, circumstances and various components of the
tumor microenvironment are discussed: