Chemotherapy: a double-edged sword in cancer treatment

Abstract

Chemotherapy is a well-known and effective treatment for different cancers; unfortunately, it has not been as efficient in the eradication of all cancer cells as been expected. The mechanism of this failure was not fully clarified, yet. Meanwhile, alterations in the physiologic conditions of the tumor microenvironment (TME) were suggested as one of the underlying possibilities. Chemotherapy drugs can activate multiple signaling pathways and augment the secretion of inflammatory mediators. Inflammation may show two opposite roles in the TME. On the one hand, inflammation, as an innate immune response, tries to suppress tumor growth but on the other hand, it might be not powerful enough to eradicate the cancer cells and even it can provide appropriate conditions for cancer promotion and relapse as well. Therefore, the administration of mild anti-inflammatory drugs during chemotherapy might result in more successful clinical results. Here, we will review and discuss this hypothesis.

Graphic abstract

Most chemotherapy agents are triggers of inflammation in the tumor microenvironment through inducing the production of senescence-associated secretory phenotype (SASP) molecules. Some chemotherapy agents can induce systematic inflammation by provoking TLR4 signaling or triggering IL-1B secretion through the inflammasome pathway. NF-kB and MAPK are key signaling pathways of inflammation and could be activated by several chemotherapy drugs. Furthermore, inflammation can play a key role in cancer development, metastasis and exacerbation.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-021-03013-3.

Introduction

Cancer is a complicated disease and many elements including genetics and environmental factors can promote its occurrence. Unfortunately, cancer prevalence has been increasing in such a way that it is categorized as the second leading cause of death after heart diseases worldwide. According to the American International Cancer Agency report, about 18.1 million new cases of cancers occurred in 2018 that almost 9.6 million of them have died so far, revealing that its treatment regimens require further attention [1, 2].

It is expected that the immune system should respond effectively against tumors through eradicating the transformed cells; however, several factors, including biological features of the tumor microenvironment (TME), result in suppression of local antitumor immune responses. Tumor cells create special conditions around themselves, paving the way for initiation, promotion, and metastasis of tumor [3, 4]. In the TME, in addition to tumor cells, other types of cells including leukocytes, stromal cells, and fibroblasts could be found. Cancer stem cells (CSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs), and mesenchymal stem cells (MSCs) are the most prominent cells in the TME [5, 6]. During the antitumor immune response, different mentioned cells produce various cytokines and chemokines leading to local inflammation. Consequently, inflammation as innate immune response can initiate and prompt adaptive immune responses to specifically combat tumor cells.

In 1863, for the first time, Rudolf Virchow defined the possible link between inflammation and cancer by identifying leucocytes in tumor-surrounding tissues. Since that time, many researchers have focused on the determination of relationship between inflammation and cancer development. Obviously, inflammatory responses, regardless of their origin, can play bilateral and challenging roles in the TME [7, 8].

Multiple types of therapies, including surgery, immunotherapy, hormone-therapy, radiotherapy, chemotherapy, and even injection of various types of RNA molecules, have been applied for cancer treatment. Among them, chemotherapy is a highly successful choice, especially for cancers complicated with metastasis. Unfortunately, chemotherapy is usually incapable to completely eradicate all cancer cells and in a short period the cancer cells may appear again. Probably, one of the major reasons leading to low efficiency of chemotherapy for certain cancers is its poverty to annihilate CSCs, which will be discussed briefly later although this is not the main goal of the current report [9, 10].

In this article, we will focus on the impact of various chemotherapy drugs as the main cancer treatment agents with pro-inflammatory properties. Afterward, we will discuss the tumor promoting effects of inflammation on different stages of cancer development, including initiation, angiogenesis, epithelial–mesenchymal transition (EMT), and metastasis. Finally, we will discuss whether inflammation is capable to increase the possibility of the recurrence of cancer through different mechanisms.

Cancer chemotherapy and the underlying mechanism of action in a nutshell

In the early twentieth century, Paul Ehrlich who was a German chemist, established chemotherapy procedures for treating infectious diseases. Simultaneously, following some experiments using animal models, he figured out that chemotherapy drugs are capable to treat cancer as well. These pioneering studies led to the development of common chemotherapy methods against different cancers [11]. Chemotherapy drugs may be administered through oral, intramuscular, or intravenous routes in order to reach systemic levels. Unfortunately, they do not have a specific antitumor activity, thus not only they inhibit the uncontrolled proliferation of malignant cells but also suppress the normal cells that possess high proliferation rates such as hair follicles, digestive tract epithelium, and bone marrow stem cells, leading to serious side effects and damages on normal cells and tissues. Therefore, their frequent administration is not recommended and considering their risk-to-benefit ratio is essential. The appropriate dosage of chemotherapeutic medications may be determined according to the number of targeted tumor cells, drug-resistance, and drug toxicity data. Finally, the efficiency of chemotherapy drugs is estimated based on the number of remaining tumor cells and the observed side effects [12–15].

Chemotherapy drugs destroy tumor cells by various mechanisms, including: (1) provoking internal and external apoptosis pathways through increasing Fas ligand (FasL) expression and consequently cytochrome C release; (2) inducing cell cycle arrest through activation of p53 gene following DNA damage and inhibition of kinases; (3) increasing autophagy pathway through signaling of the phosphatidylinositol 3-kinases/ mammalian target of rapamycin (PI3K/mTOR) and mitogen-activated protein kinase (MAPK); (4) alkylation of DNA and causing a single- or double-strand break in DNA that finally leads to cell death; (5) preventing DNA or RNA synthesis due to having a similar structure with nucleotides named antimetabolites that have higher activity in S phase of cell cycle; (6) interference with microtubules resulting in cell growth cessation; (7) causing direct or indirect DNA damages through production of reactive oxygen species (ROS); and (8) inhibition of topoisomerases and stopping cell proliferation. Most of these mechanisms lead to oxidative stress and initiation of ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) repair response, which through applying p53 and its subordinate p21 molecule may result in cell cycle arrest or accelerated senescence [16–27].

Certain chemotherapy drugs can increase inflammation in the TME

As mentioned before, a large number of chemotherapy drugs induce accelerated senescence in tumor cells through different mechanisms. Microarray studies have shown that senescent cells express several inflammatory genes that will be activated by nuclear factor-kB (NF-kB) and CCAAT/enhancer-binding protein beta (C/EBPβ) transcription factors leading to the generation of a set of various factors called senescence-associated secretory phenotype (SASP) which can increase chronic inflammation in the TME. Different inflammatory cytokines and chemokines, growth factors, and matrix metalloproteinases (MMPs) such as interleukin-1 (IL-1), IL-6, IL-8, granulocyte–macrophage colony-stimulating factor (GM-CSF), MMP-1, MMP-3, and monocyte chemoattractant protein-2 (MCP-2), are regarded as SASP molecules [26, 28–30].

The administration of some chemotherapy agents may also stimulate the inflammation process. It was shown that low doses of cyclophosphamide can induce the production of multiple inflammatory mediators, such as GM-CSF, IL-1β, IL-5, IL-10, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). In addition, it increases the recruitment of MDSCs to the TME, which leads to the suppression of immune response to tumor cells. Moreover, cyclophosphamide triggers the generation of a large amount of ROS and reactive nitrogen species (RNS) by these cells [31]. Also, acrolein as a metabolite of cyclophosphamide provokes ROS production and activates NF-kB, which is a key transcription factor in inflammatory responses. It induces the generation of inflammatory cytokines such as IL-6 and TNF-α, as well as the activation of the cyclooxygenase-2 (cox-2) [32]. Some other chemotherapy drugs such as taxanes can elicit production of TNF-α as a crucial inflammatory cytokine in breast and ovarian tumor cells [33]. Paclitaxel as a natural taxane is used for treatment of breast cancer, but unfortunately it can activate toll-like receptor 4 (TLR4), which is highly expressed in some tumor cells. This activation not only provides receptor signaling and local inflammation in the TME but also inflammation is observed in systematic levels, which may lead to increased angiogenesis, lymphogenesis, and metastasis [34]. Paclitaxel can also activate NF-kB and lead to production of various cytokines such as IL-1, IL-6, and IL-8 [35–37].

Doxorubicin as an anthracycline chemotherapy drug stops topoisomerase 2 and can damage the intestinal epithelium and subsequently cause the leakage of lipopolysaccharide (LPS) from the normal flora of the gastrointestinal tract to the bloodstream. LPS is the main ligand of the TLR4 and following attachment to its receptor, induces systematic inflammation through the activation of TNF-α signaling pathway as well as the production of ROS and various inflammatory cytokines [38, 39]. In addition, doxorubicin increases the IL-1β secretion through activation of inflammasome as well as inducing the generation of other inflammatory factors such as TNF-α, IL-6, granulocyte colony-stimulating factor (G-CSF), C-X-C motif chemokine ligand 1 (CXCL1), CXCL10, and C–C motif chemokine ligand 2 (CCL2) [40]. As mentioned before, NF-kB plays a key role in the regulation of multiple inflammatory genes and has been approved as an impressive agent in different steps of cancer and unfortunately may be activated by doxorubicin [41, 42]. Cisplatin is a platinum-based antineoplastic drug, which induces the production of ROS and various inflammatory mediators and consequently provoke inflammation in the TME. It also enhances inflammation through the activation of NF-kB and TNF-α signaling and may lead to nephropathy [43]. Furthermore, most chemotherapy drugs such as doxorubicin, etoposide, and 5-fluorouracil can trigger P38-MAPK, which is a vital signaling pathway in the production of inflammatory cytokines such as IL-1β, TNF-α, and IL-6 [44]. Table 1 and Supplementary Figure summarize some common chemotherapy drugs with the property of inflammatory response through the activation of multiple signaling pathways and production of various inflammatory cytokines.

Table 1.

Examples of inflammation-inducing chemotherapy drugs

Drug name	Cancer therapy application	Mechanism of action	Inflammatory mediators	Reference
Doxorubicin	Breast, lung, gastric, ovarian, thyroid cancers, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma	(1) Inhibition of topoisomerase-II-mediated DNA repair	(1) SASP production	[24, 179–182]
		(2) Free radicals production	(2) Inflammatory cytokines production by ZAK-dependent JNK/MAPK activation
		(3) Histone dispossession from chromatin	3) NF-kB activation
Cisplatin	Bladder, ovarian, head and neck, lung, testicular, cervical, esophageal, breast, and brain cancers	(1) DNA damage	(1) Production of TNF-α and IL1-β	[183–187]
		(2) Internal and external apoptosis	(2) ROS production
		(3) ROS production	(3) Induction of inflammation and pro-inflammatory cytokine secretion by p38-MAPK and NF-kB activation
Paclitaxel	Lung, ovarian, and breast cancers	(1) Stabilization of microtubules	(1) Upregulation of IL-1β, IL-8, IL-6, VEGF-A	[188–191]
		(2) Interfere with normal mitosis, and apoptotic cell death	(2) Activation of TLR4, NLRP3 and Inflammasome
			(3) NF-kB activation
5-Fluorouracil	Colorectal, gastrointestinal, head and neck, pancreatic, and breast cancers	(1) Prevention of cell proliferation with inhibition of the enzyme thymidylate synthase required for DNA synthesis	(1) NF-kB activation	[192–195]
			(2) Production of inflammatory cytokine such as TNF-α, IL-1β, and IL-6
Carboplatin	Lung, ovarian, and head and neck cancers	(1) Alkylation of DNA which can lead to cell death in tumor cells	(1) Enhancement of the serum level of TNF-B	[196–199]
			(2) Induction of NF-kB and inflammatory cytokine genes expression
Etoposide	Testicular and lung cancers	(1) Inhibition of topoisomerase-II	(1) NF-kB activation	[200–205]
			(2) Pro-inflammatory cytokine production
			(3) ROS production
Daunorubicin	Lymphoma, breast cancer, uterine, ovarian, and lung cancers	(1) Inhibition of topoisomerase-II-mediated DNA repair	(1) Release of IL-1β	[206–208]
		(2) Production of free radicals	(2) Activating of the NLRP3 and inflammasome
		(3) Histone dispossession from chromatin
Cyclophosphamide	Breast and lung cancers	(1) Prevention of cell division by crosslinking DNA strands	(1) NF-kB activation	[32, 209]
			(2) Inflammatory cytokine production such as TNF-α, IL-1β, and IL-6
Mitomycin C	Digestive tract cancers such as gastric carcinoma, colorectal, and pancreatic cancers	(1) DNA crosslinking	(1) NF-kB activation	[204, 210, 211]
		(2) Oxidative stress-mediated DNA damage	(2) Inflammatory cytokine production
			(3) ROS generation

Inflammation

Inflammation is a significant part of innate immune response, which is initiated by danger signals such as infections or exposure to certain chemicals. Acute inflammation strives to eliminate pathogens through the recruitment of immune cells and inflammatory proteins to the infection sites. After deletion of the stimulant, inflammation will be subsided through the negative regulatory signaling pathways to prevent damage to self-tissues [45, 46]. However, regardless of any reason, if an inflammatory response continued, homeostasis would not be established, so acute inflammation will be converted into a chronic form, i.e., failure in resilience [47, 48]. Chronic inflammation, especially when it is out of control, might increase susceptibility to development of various neoplasia. It has been reported that development of 20% of cancers is related to chronic inflammation [49] although it is still unclear for many cancers whether it is the chicken or egg. Chronic inflammation through the recruitment of different innate and adaptive immune cells as well as the generation of various cytokines and chemokines, and elicitation of the multiple signaling pathways especially NF-kB and signal transducer and activator of transcription 3 (STAT3) can affect all steps of tumorigenesis such as the initiation of neoplasia, development, and spreading of tumor cells to distant tissues, which will be discussed as following [7, 50, 51].

Inflammatory disease and cancer

Multiple inflammatory conditions may enhance cancer development risk; for example, inflammatory bowel disease (IBD) is a suggested and vital risk factor for colon cancer. Almost 5–10% of patients after 20 years and 10–12% after 30 years develop colon cancer [52]. Studies have shown that NF-kB and STAT3 are highly activated in the tumor cells and the presented ROS and NOS cause mutations and disruption of the repairing pathways [53, 54]. Another inflammatory condition is chronic obstructive pulmonary disease (COPD). Approximately 50–70% of patients with lung cancer suffer from COPD. Chronic inflammation leads to recurrent damage and subsequent induction of repair, which increases likelihood of genetic errors and EMT process that highly contributes to lung cancer [55]. Moreover, multiple inflammatory mediators such as IL-17, macrophages, neutrophils, ROS, NOS, and NF-kB play impressive roles not only in the COPD process but also in the induction and promotion of lung cancer [56–58]. Smoking is a common causative reason for both COPD and lung cancer through provoking inflammation and oxidative stress. Cigarette smoke increases the expression of the inflammatory cytokines and the inflammatory activity of lymphocytes by inducing the Cox2 enzyme [55, 59]. Cigarette smoke induces RNS, which may damage DNA, activates NF-kB to produce inflammatory cytokines, and triggers Akt and MAPK signaling pathways, which are crucial in cell proliferation and differentiation, hence can affect both COPD and lung cancer [60, 61].

Gastroesophageal reflux disease (GERD) is a risk factor for esophageal cancer by inducing local inflammation through NF-kB activation and inflammatory cytokine production [62]. In GERD, in addition to immune cells, the endothelial, epithelial, and mesenchymal cells produce inflammatory mediators such as platelet-activating factor (PAF), ROS, and IL-6 in response to the gastric contents resulting in chronic inflammation that is effective in fibrosis and carcinogenesis [63]. ROS produced by various sources such as neutrophils can damage the esophageal epithelial cells by provoking DNA mutation and lipid peroxidation, which can be linked to the characteristics of GERD, esophageal inflammation, Barrett’s esophagus, and cancer together [64].

Liver cancer is also associated with inflammation [65]. Inflammation can result from chronic viral infections such as hepatitis B and hepatitis C, or chronic consumption of alcohol [66, 67]. Chronic alcoholism induces internal and external apoptotic pathways in hepatocytes through generation of inflammatory mediators such as TNF-α, ROS, and Fas [68]. In chronic viral infections, cytotoxic T cells (CTLs) not only destroy infected cells but also provoke inflammation by production of inflammatory cytokines and evoking other inflammatory cells [69]. Therefore, there will be an inflammatory response associated to the presence of a specific stimulant, which will not be downregulated and may result in chronic liver damage with possibility enhancement of fibrosis, cirrhosis, and eventually cancer [70]. In the inflammatory/repairing processes, inflammatory signaling pathways (NF-kB and STAT3) play key roles in the linkage of inflammation to cancer and inflammatory mediators such as ROS and NOS may induce DNA damage and cancer initiation [71, 72].

Inflammation and tumor initiation

The onset of cancer usually occurs following the accumulation of mutations in the somatic and regulatory genes, including both oncogenic and tumor suppressor ones that ultimately control cell growth, proliferation, apoptosis, and DNA repair mechanisms. Free radicals of oxygen and nitrogen are inflammatory mediators or inducers that are highly present in inflammatory regions. They can increase probability of cancer development through DNA mutation mechanisms. Point mutations can result in DNA instability and if located on regulatory genes can increase the expression rate of oncogenes or tumor suppressor genes leading to transformation and malignancy. Furthermore, constant presence of nitric oxide (NO) can disrupt the efficacy of DNA repairing pathway. Inflammatory cells including neutrophils and macrophages produce too much ROS and RNS in certain circumstances, their production is increased under the influence of inflammatory cytokines such as TNF-α and IL-1β. On the other hand, inducible nitric oxide synthase (iNOS) is the main enzyme for NO generation, which is induced by NF-kB and hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathways and inflammatory cytokines such as TNF-α and IL-1β [8, 73–78]. NF-kB as an indispensable mediator in the inflammatory responses can be effective in cancer initiation through the production of various factors, including vascular endothelial growth factor (VEGF), G-CSF, GM-CSF, and transforming growth factor beta (TGF-β). All together they can lead to the protection of malignant cells from apoptosis induced by macrophages, suppression of adaptive immune response through the recruitment of MDSCs, and inhibition of CTL activity [79]. Epigenetic changes in STAT3 and Janus kinase 2 (JAK2) may increase the possibility of cancer occurrence as well. For example, phosphorylation and acetylation of the STAT3 can lead to the activation of DNA (cytosine-5)-methyl transferase-1 (DNMT1) enzyme and facilitates its attachment to the promoter region of the suppresser genes. Following the enzymatic activity of DNMT1, some gene promoters would be methylated, so their transcription rate would become off [80].

Inflammation and angiogenesis

Angiogenesis and neovascularization are essential requirements for cancer cell survival, growth, proliferation, and metastasis. Several mediators including VEGF and platelet-derived growth factor (PDGF) are capable of triggering angiogenesis in the TME [81]. HIF-1α is induced following hypoxia in the TME and is one of the main regulators of angiogenesis. This transcription factor controls the expression level of various pro-angiogenic factors [82]. It is noteworthy that multiple inflammatory mediators including, ROS [83], STAT3 [84], NF-kB [85], IL-1β [86], TNF-α [87], IL-6 [88], COX-2 and prostaglandin E2 (PGE-2) as its product [89] can induce HIF-1 and increase angiogenesis. On the other hand, inflammatory mediators can directly induce generation and release of the pro-angiogenic factors as well. For instance, neutrophil, NF-kB, STAT3, IL-1, and TNF-α provoke production of VEGF, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IL-8, and MMP-9 as the impressive elements in the angiogenesis [90–95].

Inflammation and EMT/Metastasis

Approximately, 90% of deaths in cancer is due to metastasis, which is a multi-step progressive stage including local invasion, intravasation to blood or lymphatic vessels and transfer to distant tissues, extravasation, and colonization to create the new tumor mass [96]. EMT is an essential process for metastasis during which tumor cells undergo some biological alterations, including the expression of some transcription factors such as twist, snail, zinc finger E-box binding homeobox 1 (ZEB1) as well as reduction in E-cadherin and augmentation of vimentin, which results in losing their features as epithelial cells and convert them to mesenchymal cells, being capable of separating from the primary tumor and invading some distant tissues [97]. Different inflammatory mediators can be effective in both EMT and metastasis, which will be discussed in detail. Tumor cells produce TNF-α and GM-CSF triggering neutrophils to release HGF, which help the migration of tumor cells to distant tissues. In addition, in breast cancer, GM-CSF is generated by tumor cells and induces the production of the oncostatin-M (OSM) by neutrophils that results in generation of VEGF by tumor cells and rise of invasion [98]. Alternatively, neutrophils by production of hypochlorous acid (HOCl) during the respiratory burst induce MMP2,7,8,9 and impede their inhibitors called tissue inhibitors of metalloproteinases (TIMPs) and increase metastasis of the tumor cells [99]. Furthermore, neutrophils upregulate expression of multiple transcription factors affecting EMT and production of mesenchymal proteins, including snail, twist, ZEB1 and N-cadherin, alpha smooth muscle actin (α-SMA), fibronectin, and vimentin through production of neutrophil elastase as well as secretion of TGF-β [100, 101]. Monocyte (Mo) is another inflammatory cell which is recruited to the metastatic TME by CCL2 and helps tumor cells to exit the vessels and colonize in the distant tissues through generation of VEGF [102]. On the other hand, CCL2 dephosphorylates vascular endothelial (VE)-cadherin that leads to disruption of vascular endothelial integrity and, thereby, increase penetration of cancer cells. In addition, both inflammatory cells by the production of various inflammatory mediators such as cytokines, ROS, and MMPs enhance the expression of adhesion molecules on endothelium, increase vascular permeability, and disrupt endothelial integrity [103]. TNF-α through activation of NF-kB induces snail, slug, and twist in non-small-cell (NSC) lung, head and neck, and hypopharyngeal cancers, respectively [104–106]. TNF-β is another inflammatory isoform, which induces EMT in colorectal cancer through NF-kB and focal adhesion kinase (FAK) [107]. The inhibition of NF-kB signaling in CSCs decreases several transcription factors affecting EMT, including twist1, snail, slug, ZEB2; and consequently limits the invasion of tumor cells [108]. IL-1β as a vital inflammatory cytokine may play an impressive role in metastasis of different cancers, including breast [109], NSC lung [110], colon [111], and liver cancers [112]. In addition, IL-6 is produced by different cells in the TME of bladder [113], lung [114], gastric [115], colon [116], breast [117], and pancreas cancers [118]. This may enhance EMT and metastasis by activation of STAT3 as an efficient factor in metastasis. STAT3 plays a critical role in the metastasis through multiple mechanisms, including: (1) upregulating the expression of different MMPs (MMP1,2,7,9) that support escaping the tumor cells from primary tumor mass and entering the vessels by destroying the extracellular matrix (ECM) and endothelium of the vessels, respectively; (2) affecting intracellular molecules such as Rho, Rac, stathmin, which play impressive roles in the cell migration; (3) suppressing the immune system and maintaining tumor cells during the migration; (4) expressing various factors affecting EMT such as twist, snail, and ZEB1 [94, 119]. Another inflammatory element is ROS, which can trigger MAPK and PI3K/Akt signaling pathways and induce transcription factors such as HIF1-α and snail to enhance metastasis [120]. In addition, PGE2 as an inflammatory product provokes PI3k/Akt and extracellular signal‐regulated kinases 1/2, p38 and mitogen‐ and stress‐activated protein kinase‐1 (ERK1/2/p38/MSK‐1) signaling pathways that lead to an augmentation of COX-2 and HIF in tumor cells and increased possibility of metastasis [121].

Inflammation and cancer development/progression

Inflammatory mediators not only can expand cancer by affecting each aforementioned crucial steps, but also can exacerbate the process by suppressing the immune response, inducing tumor cell proliferation, and inhibiting their apoptosis. Tumor cells can activate STAT3 in immune cells through the production of various cytokines and growth factors, which can suppress CTLs, natural killer (NK) cells, and dendritic cells (DC) against tumor cells, as well as the generation of inhibitory cytokines and recruitment of the regulatory T cells (Tregs) and MDSCs that all of them are ended in the immunosuppression and tumor cell surveillance [122]. IL-6 is an important cytokine, which triggers the JAK/STAT3 signaling pathway, thereby induces the production of MCP-1 from endothelial cells that recruit neutrophils and macrophages into the TME and induces the development of the M2 phenotype. This cytokine also represses the immunity by inhibiting DCs and recalling more regulatory cells [123]. On the other hand, STAT3 regulates many other genes that have impressive effects on the cell cycle, proliferation, and apoptosis resistance of genes including cyclin D1, c-Myc, B-cell lymphoma-extra-large (Bcl-xL), B-cell lymphoma 2 (Bcl-2), and survivin leading to tumor growth and resistance to the treatment [124]. Therefore, inhibition of STAT3 provokes apoptosis and cell cycle arrests in different cancers such as esophageal [125, 126], prostate [127], lung [128, 129], colon [130], and colorectal cancers [131].

The NF-kB pathway can be activated through mutation of the regulatory genes of this pathway, mutations in the sequence of oncogenes, or following various signaling cytokines in the TME. NF-kB is a transcription factor that regulates gene expression of different cytokines, chemokines, adhesion molecules responsible for apoptosis resistance and cell cycle control. NF-kB and STAT3 may synergize each other and increase expression of the common target genes. Rel A is a subunit of NF-kB and due to its activity, TAMs can escape from apoptosis induced by CTLs [132]. PGE2 in the TME inhibits differentiation, recruitment, and activity of DCs and increases the development of M2 macrophages and MDSCs that all together result in immunosuppression and tumor growth [133]. Besides, PGE2 through provoking Wnt/β-catenin in tumor cells induces cancer cell proliferation and invasion in endometriosis-induced cancers [134]. Another efficient inflammatory element is ROS that activates multiple signaling pathways including PI3K/Akt/mTOR/MAPK/ERK and triggers NF-kB/nuclear factor erythroid 2-related factor 2 (NRF2) transcription factors, which leads to enhancement of tumor growth and maintenance. Also, NF-kB /NRF2 transcription factors prevent cancer cell death by inducing the expression of antioxidants [120]. Another effective immunosuppressive mechanism in cancer promotion is the exhaustion of immune cells. Chemotherapy drugs may directly induce exhaustion or indirectly induce chronic inflammation [135, 136]. We have summarized the effects of inflammation in different steps of cancer in Fig. 1. In addition, we have listed some important inflammatory mediators that are highly presented in the TME and briefly mentioned their key roles in different steps of cancers (Table 2).

Fig. 1.

Effects of inflammation in different stages of cancer, including initiation, angiogenesis, EMT, and metastasis. ROS and NOS can cause DNA damage and mutations in somatic or regulatory genes leading to the transformation. ROS and NOS production is increased by various inflammatory cells, cytokines, and transcription factors including neutrophil (Neu), monocyte (Mo), IL-1B, TNF-α, NF-kB, and HIF. Besides, epigenetic alterations in STAT3 activate DNMT1, as a result, which represses activity of suppressor genes. Angiogenesis is crucial for tumor growth and can be increased by inflammatory mediators either directly or indirectly. Neutrophils induce generation of angiogenic factors directly. While, IL-6, COX-2, and ROS induce HIF-1, which consequently provoke expression of angiogenic factors. However, NF-kB, STAT3, IL-1β, and TNF-α increase angiogenic factors in both ways. Prolyl hydroxylase (PDH) is an enzyme that adds ubiquitin to HIF-1 and causes degradation but can be inhibited by ROS. EMT is a biological procedure essential for metastasis. ROS induce EMT transcription factors through Akt/PI3K/MAPK. It also produces urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), which degrade endothelial integrity and blocks tissue inhibitors of metalloproteinase (TIMPs), to prevent the inhibition of MMPs. Tumor cells recruit neutrophils by releasing TNF-α and GM-CSF. Although neutrophils induce EMT through the TGF-β pathway, they produce MMPs and blocks TIMPs. Neutrophils and monocytes induce the expression of adhesion molecules on endothelial cells, consequently affecting intravasation and extravasation of tumor cells. Monocytes produce MMPs and VEGF as well. Cytokines such as IL-6, TNF-α/β, and IL-1β provoke EMT transcription factors through activation of STAT3, NF-kB, MEK, ERK, and JNK

Table 2.

The effects of various inflammatory mediators in different steps of cancer development

Inflammatory mediators	Cancer initiation	Angiogenesis	EMT and metastasis	Promotion	Reference
ROS	DNA damage	(1) Induce HIF-1a	(1) Integrin activation	(1) Activate PI3K, Akt and MAPK, NF-kB to induce cell proliferation and apoptosis protection	[212, 213]
		(2) Stabilize HIF-1a by inhibiting prolyl hydroxylase	(2) Induce cell migration by activating MAPK, PI3K/Akt, PKC, and FAK	(2) Increase the amount of cyclins like B2, D3, E1, E2 which induce G1 to S transition
		(3) Activate VEGF receptors	(3) Induce expression of uPA, involved in cellular invasion
			(4) Modulating actin cytoskeleton
			(5) Proteolytic degradation of ECM components by production of MMP. TIMP, uPA
PGE2		(1) Induce VEGF production through JNK1 by ERK2	Induce metastasis in different cancers like ovarian cancer prostate cancer and breast cancer	(1) Suppress immunity	[148, 214–218]
		(2) Activate endothelial cells (EC)
		(3) Induce HIF1-a
TNF-α	ROS and RNS production	(1) Induce expression of angiogenic factors such as VEGF, bFGF, IL-8	(1) Induce adhesion molecules	(1) Increase number of breast cancer stem-like cells	[87, 104–106, 219–224]
		(2) Triggering Akt pathway to induce EC migration and angiogenesis	(2) Induce MMP2,3,9,12	(2) Activate inflammatory pathways like NF-kB and MAPK
		(3) Inducing HIF-1a	(3) Induce activation of FAK	(3) Regulate inflammatory gens like cytokines, chemokines and anti-apoptotic proteins
			(4) Induce different EMT transcription factor like snail, slug, twist through NF-kB activation
			(5) Induce EMT by synergizing TGF-β pathway
IL-1B	(1) ROS and RNS production	(1) Induce angiogenic factors like VEGF	(1) Induce adhesion molecules	(1) Suppress adaptive immunity by MDSC, TAM, TAN	[225–230]
		(2) Increase VEGFR2	(2) Increase EMT through NF-kB activation	(2) Induce CSC proliferation and stem cell markers
		(3) Induce HIF1-a	(3) Promote EMT through zeba/2 and reduce E-cadherin
IL-6	1) ROS and RNS production	(1) Produce VEGF	(1) Induce EMT by synergizing TGF-β pathway	(1) Activate JAK/STAT signaling to induce tumor proliferation and stop apoptosis	[88, 123, 224, 231–233]
	(2) Hypermethylation of tumor suppressor genes	(2) Induce HIF-1a	(2) Activate NF-kB to induce EMT transcription factors (Snail1, Snail2, Twist, ZEB1, and ZEB2)	(2) Induce non-cancer cells to CSC
	(3) Hypomethylation of LINE-1		(3) Activate JAK/STAT3 to induce snail	(3) Increase CSC proliferation and inhibit apoptosis through STAT3 and HIF1-a
			(4) Increase invasion through STAT3 and HIF1-a	(4) Promote tumor growth by suppressing immunity through JAK/STAT3 signaling
			(5) Increase EMT and chemo-resistance by activation of STAT3/HIF-1a/snai1pathway
NF-ΚB	(1) Suppress native and adaptive immunity	(1) Increase angiogenic factors like VEGF, IL-8	(1) Increase CD44 expression result in invasion in breast cancer	(1) Induce anti-apoptotic gens like Bcl2, bcl-xl, survivin	[79, 95, 234–238]
	(2) Augment ROS levels through inducing expression of SOD, GPx, and GST	(2) Increase MMP2,3,9	(2) Regulate different EMT transcription factors	(2) Induce cell cycle development by triggering c-Myc, cyclins D1, E
		(3) Induce HIF1-a	(3) Induce MMP expression	(3) Maintain CSC
			(4) Induce Cell adhesion molecules expression	(4) Increase breast cancer cells proliferation by increasing CD44 expression
STAT3	(1) Induce epigenetic alteration resulting in transformation	(1) Induce HIF1-a	(1) Induce different MMP like 1.2,7,9	(1) Promote tumor growth by inducing secretion of IL-6 and IL-10 family	[80, 94, 123, 239–241]
	(2) Induce mitochondria ROS production	(2) Induce angiogenic factors like VEGF, bFGF, HGF, CCL5	(2) Induce different transcription factors involved in EMT like snail, ZEB, twist	(2) Maintain CSCs
			(3) Activation of FAK to induce cell migration	(3) Inhibit apoptosis by inducing anti-apoptotic genes like Bcl-2, Bcl-xL, MCL1
				(4) Promote cell proliferation by inducing c-Myc, cyclin D1

Inflammation and cancer recurrence

As mentioned earlier, unfortunately, chemotherapeutic drugs are inefficient to eradicate all CSCs, which may have a key role in cancer relapse. CSCs are a small population of tumor cells, which is believed to be responsible for cancer initiation and have some features and capabilities similar to other stem cells, including self-renewal, high proliferation rate, and differentiation into multiple lineages [137, 138]. They are usually resistant to chemotherapy drugs through different mechanisms including (1) expression of ATP-binding cassette (ABC) family of transporters that helps in expelling the chemotherapeutic drugs from the cell; (2) excessive expression and activity of the cytosolic enzyme, aldehyde dehydrogenase (ALDH), which oxidizes intracellular aldehydes; (3) expression of proteins that confers apoptosis resistance properties; (4) high activity of Wnt/β-catenin/ hedgehog/notch signaling pathways, which provides them self-renewal and differentiation abilities; (5) high restorative power following DNA damage; and (6) remaining latent in G0 phase of cell cycle that helps them escape from chemotherapy drugs [139–141]. So according to all of these mechanisms, there is a strong probability that CSCs remain alive after chemotherapy and can reenter to G1 phase and resume proliferation to create new tumor masses. We discussed earlier that chemotherapy drugs can enhance inflammation in the TME. Now, it is important to say that various inflammatory mediators can have a significant role in provoking CSCs to resume proliferation, which leads to cancer relapse as well. For instance, NF-kB activation and consequently production of inflammatory cytokines (IL-1, IL-6, TNF) can induce slug, twist, and snail transcription factors, which pave the way for increasing the CSC phenotype and the EMT process [142]. In addition, NF-kB is highly expressed in CSCs, enhancing their proliferation, and inducing apoptosis resistance [143, 144]. It has also been shown that the inhibition of this factor in lung cancers can reduce the expression of stemness-related genes such as SRY-box transcription factor 2 (Sox2) and octamer-binding transcription factor 4 (Oct4) as well as anti-apoptosis genes, which can reduce self-renewal, proliferation ability, and apoptosis resistance, respectively [108]. Another noteworthy point is that STAT3 plays a critical role in the preservation of CSCs. Its activation is related to CSC markers, including Oct 3/4 and Nanog expression and maintenance of stem-like properties [145]. It should be considered that various inflammatory mediators such as STAT3 [146], NF-kB [147], and PGE2 [148] induce immune suppression through different mechanisms. As mentioned before, some of these mediators such as ROS, and various cytokines including TNF-α, IFN-γ, IL-1β, IL-5, IL-10, and GM-CSF trigger recruitment of MDSCs to the TME [31], which can repress immunity in different ways such as: (1) inhibition of T cells through deprivation of the essential amino acids such as L-arginine and cysteine in the TME [149, 150]; (2) repressing T cells by production of ROS and RNS, which down-regulates T-cell receptor-associated zeta chain; (3) prevention of MHC-peptide recognition by addition of nitrite molecules to the T-cell receptor (TCR) or major histocompatibility complex (MHC) [151–153]; (4) disruption of the naïve T cells and migration of CTLs following reduction in L-selectin (CD62L) and CCL2 alteration through peroxynitrite generation [154, 155]; (5) increasing the number of Tregs [156–158]; and (6) inhibition of NK cells [159].

Therefore, there will be an appropriate immune-suppressed environment for remaining CSCs. Hence, they can restart to proliferate without any hassle, which may lead to cancer relapse (Fig. 2).

Fig. 2.

Several Chemotherapy drugs cannot eradicate cancer stem cells and even provoke their proliferation and might cause cancer relapse. Chemotherapy drugs eradicate tumor cells by inducing DNA damage, cell cycle arrest, apoptosis, autophagy, microtubule interference, senescence, and topoisomerase inhibition. However, cancer stem cells (CSCs) are resistant to chemotherapy due to G0 latency, high ability of DNA repair, apoptosis resistance, and high expression of ABC transporter family and aldehyde dehydrogenase (ALDH) enzyme. NF-kB and STAT3 induce the expression of anti-apoptotic proteins, resulting in apoptosis resistance. Both transcription factors control expression level of multiple genes that maintain CSC phenotype (Sox2, Oct3/4, Nanog, c-Myc) and cell proliferation (cyclin-D1). In addition, PGE2 induces signaling pathways provoking CSCs self-renewal. Alternatively, various inflammatory factors recruit the MDSCs to the TME, which led to the suppression of immune cells. Thus, there will be appropriate conditions for CSCs to proliferate and make a new cancer mass that results in cancer relapse

The effects of chemotherapy on the adaptive immune system

Adaptive immune cells along with native immune cells play key roles in combating cancers. Many studies confirm the roles of CTLs and T helper (TH) cells in fighting against tumor cells and conversely show that Tregs as the immunosuppressive population of T cells can aid tumor progression [160]. Meanwhile, there has been much less attention to B cells and humoral immunity effects on cancer cells up to now. Similar to T cells, B cells may have dual effects on cancer cells. For instance, some studies showed that B cells could improve tumor growth through different mechanisms including secretion of inhibitory cytokines (IL-10, TGF-β, IL-35), inducing PD-1/PD-L1 signaling, and activation of lymphotoxin/ IKKa-BMI1 signaling pathway [161]. On the other hand, B cells could defend tumor cells through antibody production, cytokine secretion, and presenting antigen to T cells as an APC. This duality can be justified through observation of various subsets of B cells derived from different TME after diverse treatment methods [162]. Administration of some chemotherapy drugs like anthracyclines can lead to depletion of lymphocytes specially B cells [163]. Studies in breast cancer patients show that doxorubicin can increase the number of cytotoxic T cells and NK cells while significantly reduces B cells [164]. Similarly, after administration of gemcitabine in animal model a decrease in B-cell numbers and a suppression in antigen-specific IgG responses occurs, while it provokes T-cell response. Thus, it seems that B cells are more sensitive to the anti-proliferative features of gemcitabine [165]. Common chemotherapy drugs, in addition to direct effects on cancer cells, can also influence immune cells which highly depends on the type, dose, and administration schedule of the these drugs [166]. Administration of maximum tolerated dose of chemotherapy drugs may have strong suppressive impacts on immunity including lymphocyte ablation, myeloablation, and reducing the number of effector cells such as CD8⁺ and CD4⁺ T cells as well as NKs. While administration of low doses of chemotherapy drugs may conversely potentiate immune response through decreasing inhibitory cells (MDSCs, Tregs) and increasing effector cells [167]. Cyclophosphamide is a good example for investigating the impact of dose-dependency features. Administration of low doses of cyclophosphamide reduces IL-10, and TGF-β-producing regulatory cells while increases the number of effector cells [168, 169]. Cyclophosphamide also skews M2 responses in to M1 and increases secretion of IL-6, IL-12, and ROS [170]. Other drugs like epothilone B, taxol, and vinblastine augment the expression of MHC class I molecules leading to more efficient antigen presentation [171]. In addition, 5-Fluorouracil increases Fas expression on tumor cells, making them more sensitive to lysis by CTLs. Some chemotherapy drugs can increase secretion of TH1-related cytokines and induce generation of memory T cells [172]. Besides, chemotherapy drugs can influence on immune system via other mechanisms including: (1) induction of apoptosis pathways in tumor cells which may lead to immunologic cell death (ICD), (2) direct or indirect induction of immune response, and (3) disruption of scape mechanisms in tumor cells [173]. Some chemotherapy drugs including anthracyclines, platinum compounds, alkylating agents, antimetabolites, topoisomerase inhibitors, and microtubule poisons are able to induce ICD. The mentioned drugs induce endoplasmic reticulum (ER) stress in tumor cells which leads to the presentation of Calreticulin (CRT) chaperon on tumor cell surface and consequently its recognition by phagocytic cells and also provoking immune response. ATP is another molecule released from dying tumor cells leading to augmentation of immune response. In addition, ATP activates P2X7 receptor on phagocytic cells which leads to secretion of active IL-1B through inflammasome induction. IL-1B triggers the release of IL-17 from Tγδ cells resulting in development and infiltration of IFNγ producing CTLs. Dying cells can release other markers such as HMGB-1, HSP70, HSP90, and type 1 IFNs that all can trigger various immune cells and potentiate immune response [167, 174–176]. It is noteworthy to say that some chemotherapy drugs such as mitomycin C (MMC) induce classic pathway of apoptosis but is not capable to induce immune response. Melphalan is another chemotherapy drug which is used to treat multiple myeloma and sever melanoma. Local administration of melphalan along with TNF-α leads to secretion of a huge amount of inflammatory mediators and also recruitment of inflammatory cells to the tumor site, which can promote tumor progression through inducing NF-КB signaling pathway [173].

Chemotherapy along with immunotherapy

Combination of different therapeutic mechanisms can increase the efficiency and quality of the treatment and prevent recurrence of the cancer. Previously, it was assumed that chemotherapy drugs are immunosuppressive but gradually by discovering various effects of different chemotherapy drugs on immune system, the idea was modified. Nowadays, administration of chemotherapy drugs along with immunotherapy agents is in the center of attention. Chemoimmunotherapy can neutralize the immunosuppressive impacts of chemotherapy drugs or increase their immunostimulatory features [177]. Considering the effects of some chemotherapy drugs on inducing or increasing immune response that was discussed in previous part choosing a suitable chemotherapy drug with an appropriate dosage and suitable administration schedule can lead to increased efficiency of the therapy. For instance, multiple chemotherapy drugs including 5 fluorouracil, gemcitabine, paclitaxel, cisplatin, oxaliplatin, carboplatin, irinotecan, doxorubicin, etoposide, and docetaxel can increase PDL-1 expression on tumor cells which is an inhibitory immune checkpoint and suppress effector T cells activation. Surely, application of these chemotherapy drugs along with monoclonal antibodies to PDL-1 can lead to more desirable results [178].

Concluding remarks

Cancer, as the second cause of death, kills millions of people every year. Unfortunately, this high mortality rate may indicate the ineffectiveness of several therapy protocols. Chemotherapy has long been used as the main treatment method for different types of cancers worldwide. Evidence shows that chemotherapy inefficiency in some cancer treatments might be due to provoking chronic inflammation. In fact, various chemotherapy drugs can increase inflammation in the TME leading to a more suitable environment for tumor cell growth, proliferation, and even relapse after complete remission. We believe and hypothesize that besides chemotherapy regime, simultaneous anti-inflammatory drugs administration may provide a better result in some cancer treatments, which needs of course more investigation and validation through various in vitro and in vivo experiments both preclinically as well clinically.

Supplementary Information

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Authors' contribution

All authors had substantial contributor in data mining and writing the text and have read and approved the final manuscript. The study is guaranteed by corresponding author.

Funding

This study was partly supported by grant number 16572 from Iran University of Medical Sciences, Tehran, Iran.

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The authors declare that they have no competing interests.

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