The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment

Abstract

The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane–membrane, ligand–receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells.The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect.The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor–host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver—as a critical organ that produces the leading inflammatory markers described to date—will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

Inflammation-Related Signature Profile Expression as a Poor Prognosis Marker after Oxaliplatin Treatment in Colorectal Cancer

“…This scenario could be explained as primary-derived colorectal tumourspheres efficiently responding to oxaliplatin treatment, maintaining tumoursphere formation but also increasing CSCs and stemness marker mRNA expression. It is worth noting that tumoural cells change the tissue architecture, which causes stress in the cells of stroma and induces the release of soluble inflammatory mediators and growth factors [ 12 , 15 ]. These factors maintain an inflammatory microenvironment, promoting tumorigenesis.…”

“…Inflammatory mechanisms are mediated by different immune cells through different cytokines, chemokines, and other proinflammatory molecules, which trigger cell progression, hyperplasia, and metastasis [ 14 , 15 ]. These inflammatory mechanisms are mediated by interleukins and their receptors, creating an interconnection between tumour and immune cells [ 15 ].…”

“…Inflammatory mechanisms are mediated by different immune cells through different cytokines, chemokines, and other proinflammatory molecules, which trigger cell progression, hyperplasia, and metastasis [ 14 , 15 ]. These inflammatory mechanisms are mediated by interleukins and their receptors, creating an interconnection between tumour and immune cells [ 15 ]. In fact, CRC tumour cells release not only chemokines, which can recruit essential immune cells for the inflammatory process, but also interleukin, which allow the tumour cells to avoid apoptosis, trigger metastasis, and increase the cancer stem cell (CSC) population [ 12 , 15 , 16 ].…”

“…These inflammatory mechanisms are mediated by interleukins and their receptors, creating an interconnection between tumour and immune cells [ 15 ]. In fact, CRC tumour cells release not only chemokines, which can recruit essential immune cells for the inflammatory process, but also interleukin, which allow the tumour cells to avoid apoptosis, trigger metastasis, and increase the cancer stem cell (CSC) population [ 12 , 15 , 16 ]. Furthermore, inflammation plays a critical role in CSC self-renewal as well by cytokine signalling pathways triggered by interleukin-6 (IL6), CXCL8, and interleukin-20 (CCL20), among others [ 16 ].…”

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…Exosomes, saucer-shaped extracellular vesicles of approximately 30–100 nm diameter that are delimited by a lipid bilayer, contain a large amount of biologically active molecules, such as lipids, enzymes, metabolites, and various non-coding RNAs (miRNAs, long noncoding RNAs, and circular RNAs) ( Yu et al, 2021 ), and play important roles in cell-cell communications in TME ( Aguilar-Cazares et al, 2022 ; Ghosh and Ghosh, 2022 ). In addition, due to the excellent biosafety, low immunogenicity, carrier properties, nanoscale penetration effect, longer half-life, and no microvascular embolism ( Ghosh et al, 2020 ), numerous studies have shown that as a carrier of conventional chemotherapy drugs ( Zhao et al, 2021 ; Premnath et al, 2022 ), targeted therapy ( Deng et al, 2021 ; Xu et al, 2021 ), or mediate photodynamic therapy and immunotherapy ( Jang et al, 2021 ), exosomes have shown potential as a new NDDS for the treatment of PC.…”