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. 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.

Keywords: Cancer; Chemotherapy; Inflammation; Metastasis; Tumor microenvironment.

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

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