2. Immune cells:
The immune system plays a crucial role in monitoring cancer and
responding to chemotherapy. Myeloid-derived suppressor cells (MDSCs),
tumor-associated macrophages (TAMs), dendritic cells (DCs), regulatory
and effector T cells, B cells, and natural killer cells (NKs) are the
main immune cells present in the TME [15, 164]. These cells can have
either opposing or stimulating effects on the tumor and play a key role
in tumorigenesis [15]. Immune cells also contribute to the
development of chemoresistance [165]. According to several studies,
the relationship between MDSCs and malignant cells has a significant
impact on chemotherapy resistance and immune system suppression [112,
166, 167]. At different stages of tumor development, diverse
populations of T cells are observed in the tumor microenvironment
[168, 169]. An increase in T-regulatory lymphocytes (T-reg)
infiltration in the tumor microenvironment is associated with
chemoresistance in several types of cancer, including colorectal, lung,
kidney, HNSCC, melanoma, ovarian, and glioblastoma cancer [170-176].
Evidence suggests that tumor cells may manipulate local DCs to form
suppressive T cells, ultimately leading to drug resistance [177,
178]. Drug resistance and tumor progression can be caused by high
infiltration of tumor-associated neutrophils (TANs) in the TME
[179]. TANs can lead to acquired drug resistance in cancer due to
their capacity to increase angiogenesis, increase tumor cell
proliferation, and suppress the immune system [180, 181]. Moreover,
TANs can reduce the efficacy of many cancer drugs such as common
cytotoxic drugs and immune checkpoint inhibitors by activating various
signaling pathways [168]. Although NK cells may exhibit multi-drug
resistance-like activity, according to studies, this property can be
inhibited by drugs such as solutol HS-15 or verapamil [168,
182-184].
TAMs are derived from circulating monocytes and are one of the most
abundant cells in solid tumors that have a significant impact on
suppressing the immune system in the TME, furthermore,
TAMs play a role in
chemoresistance and tumor development [111]. Among the immune cells
present in the TME, macrophages have a prominent and critical role in
chemoresistance due to their capabilities and high numbers. TAMs are the
most abundant among immune cells in the TME, and their increased
infiltration into the microenvironment leads to unfavorable outcomes in
chemotherapy [112, 185, 186]. Generally, TAMs are divided into two
subgroups, M1 and M2, with the M2 phenotype playing a role in promoting
drug resistance and tumor progression [112, 187]. In cancer
conditions, macrophages are educated by the TME, and TAMs are usually
polarized from M1 to M2 [188]. Due to the interaction between TAMs
and tumor cells, under the pressure of treatment, TAMs are promoted by
tumor cells and differentiate into immunosuppressive M2-polarized
macrophages, leading to therapeutic resistance [112]. Moreover,
studies have demonstrated the type of M2 can lead to acquired drug
resistance in cancer cells [189-191].
TAMs, like CAFs, release a wide range of soluble factors in the TME,
including chemokines, enzymes, interleukins, exosomes, etc, to combat
drug attacks, for instance, TAMs can prevent paclitaxel-induced tumor
cell death by expressing cathepsin S and B [112]. Moreover, through
overexpressed cytidine deaminase or CDA (an enzyme that is involved in
gemcitabine degradation), TAMs can promote chemotherapy resistance in
cancer [165, 192]. By secreting exosomal miR-365, TAMs can increase
the metabolism of gemcitabine in cancer cells, which ultimately leads to
apoptosis inhibition and tumor resistance promotion [193, 194]. TAMs
upregulate Gfi-1 in tumor cells by TGF-β secretion, which ultimately
leads to reduced sensitivity of tumor cells to gemcitabine by inhibiting
HMGB1 (high mobility group box 1) and CTGF (connective tissue growth
factor) expression [195]. By expressing IGF, TAMs can cause
resistance to chemotherapy with albumin-binding paclitaxel and
gemcitabine [165, 196]. Additionally, TAMs can cause chemotherapy
resistance in pancreatic cancer by inducing EMT [197]. According to
evidence from prostate cancer treatment with ADT, CSCs can remodel
macrophages into TAMs, subsequently, through the IL6/STAT3 signaling
pathway, TAMs can increase stem-like features of CSCs and drug
resistance [112, 198].
Overall, TAMs use various mechanisms to induce drug resistance,
including regulating CSC properties, transforming into M2 suppressive
phenotype, promoting EMT, releasing various cytokines, and suppressing
immune cells [112].
3. DNA repair mechanisms:
Preserving the genome and transmitting a healthy genome to the next
generation is an essential task for living organisms [199]. However,
DNA is constantly exposed to both endogenous insults (such as
intracellular free radical oxygen species (ROS), etc.) and exogenous
genotoxic insults (such as ionizing radiation (IR), ultraviolet (UV)
radiation, chemotherapeutic drugs, etc.), that can damage to DNA
[199]. Although DNA damage is a crucial target for radiotherapy and
chemotherapy, it can also lead to the development of cancer [199].
Therefore, to maintain genome integrity, living organisms rely on a
complex system and multiple mechanisms to counteract DNA-damaging
factors, collectively known as the DNA Damage Response (DDR) [200].
Several DNA repair pathways are utilized to counteract DNA damage,
including:
(1)
Base excision repair (BER), (2) Nucleotide excision repair (NER),
(3) Homologous recombination (HR), (4) Non-homologous end joining
(NHEJ),
(5) Mismatch repair (MMR), (6) Microhomology-mediated end joining
(MMEJ),
(7) DNA damage tolerance (DDT) (Translesion synthesis (TLS), template
switching (TS)),
(8) \(O^{6}\)-methylguanine-DNA methyltransferase (MGMT) pathway,
(9) Fanconi anemia (FA) pathway, (10) Single-strand annealing (SSA)
[200-203]
Among these pathways, BER, MMR, NER, HR, and NHEJ are the major and
essential pathways in DNA repair [200, 201].
Moreover, there are several types of DNA damage, including:
(1)
Clustered damaged sites, (2) Base damage, (3) Single-strand breaks
(SSBs),
(4) Double-strand breaks (DSBs), (5) Sugar damage, (6) DNA
cross-linkingĀ [204]
DSBs are the most destructive and the most deleterious type of DNA
damage for cells which can bring about cell death or carcinogenesis
[204]. Among the types of DNA damage, SSBs and DSBs are prominent
which can bring about genome rearrangement. The direct and indirect BER,
MMR, and NER pathways repair SSBs damage, while the SSA, NHEJ, and HR
pathways repair DSB damages [200, 205, 206]. Moreover, DNA adducts
and replication errors are repaired by the NER and MMR pathways,
respectively [200].
To control the DDR, cells utilize epigenetics and miRNAs as regulators.
Epigenetic alterations in gene expression and tumor heterogeneity play a
key role, as a result, epigenetic chromatin regulation can influence the
mechanisms and pathways involved in the DNA repair process [207].
Histone deacetylases (HDACs) can contribute to the preparation of
chromatin for DSB repair promotion via NHEJ and HR [207].
Furthermore, DNA methylation is a common epigenetic mechanism in cancer
cells and gene inactivation [207]. Alterations in gene promoter
methylation status of DDR components are observed in diverse cancer
types including oral squamous cell carcinoma, thyroid cancer, non-small
cell lung cancer (NSCLC), neck squamous cell carcinoma, gastric cancer,
acute myeloid leukemia (AML), breast cancer, ovarian cancer, bladder
cancer [207-218]. Moreover, the methylation status of some DDR genes
can be employed as treatment response, prognostic, and diagnostic
biomarkers in diverse types of cancer [207]. miRNAs function as
regulators in various processes, including tumorigenesis, and
post-transcriptional control of DNA repair components, in addition,
miRNAs can regulate the expression levels of DNA repair genes and
subsequently modulate the sensitivity of cancer cells to DNA-damaging
agents [207].
Chemotherapeutic agents commonly used include Topoisomerase I
inhibitors, Alkylating agents (such as cisplatin), and DNA Topoisomerase
II inhibitors [219]. During chemotherapy using Camptothecin (a
Topoisomerase I inhibitor), if SSB damage occurs, the BER pathway is
activated, and subsequently, PARP1 and APE1 enzymes are activated,
however, if DSB damage occurs, the HR and NHEJ pathways are activated,
followed by the HR pathway activating AMT and CHK1 enzymes, and NHEJ
activating DNA-PK enzyme [202]. When Etoposide (a Topoisomerase II
inhibitor) is prescribed, DSB damage occurs, which activates the HR and
NHEJ pathways [202]. The HR pathway activates ATM and CHK1 proteins,
and NHEJ activates DNA-PK [202]. When Cisplatin (an Alkylating
agent) is prescribed, DNA interstrand cross-link (ICL) damage
(activating HR and NER pathways) and intrastrand cross-link damage
(activating NER pathway) occur [202]. Then, the HR pathway activates
ATM and CHK1 proteins, and the NER pathway activates XPA, XPB, and XPG
proteins [202].