Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

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Inflammation and tumor progression: signaling pathways and targeted intervention.

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

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Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.

The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly challenge the overall clinical outcome of promising therapies need to be fully identified and counteracted. Although cancer immunotherapy has increasingly been applied, we are far from understanding how to utilize different strategies in the best way and how to combine therapeutic options to optimize clinical benefit. This review intends to give a contemporary and detailed overview of the different roles of immune cells, exosomes, and molecules acting in the tumor microenvironment and how they relate to immune activation and escape. Further, current and novel immunotherapeutic options will be discussed.

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The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.

https://www.pnas.org/content/pnas/116/39/19609.full.pdf

Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells.

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.

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The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis.

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies.

https://www.mdpi.com/2072-6694/11/4/564/pdf

Tumor-Associated Neutrophils in Cancer: Going Pro.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC.

https://www.mdpi.com/2072-6694/11/3/290/pdf

Cancer-Associated Fibroblasts' Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma.

Recent evidence suggests that interactions among proinflammatory cytokines, chemokines, and cancer cell–recruited neutrophils result in enhanced metastasis and chemotherapy resistance. Nonetheless, the detailed mechanism remains unclear. Our aim was to discover the role of IL-17, CXC chemokine receptor 2 (CXCR2) ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast cancer. Mice were injected with Cl66 murine mammary tumor cells, Cl66 cells resistant to doxorubicin (Cl66-Dox), or Cl66 cells resistant to paclitaxel (Cl66-Pac). Higher levels of IL-17 receptor, CXCR2 chemokines, and CXCR2 were observed in tumors generated from Cl66-Dox and Cl66-Pac cells in comparison with tumors generated from Cl66 cells. Tumors generated from Cl66-Dox and Cl66-Pac cells had higher infiltration of neutrophils and T helper 17 cells. In comparison with primary tumor sites, there were increased levels of CXCR2, CXCR2 ligands, and IL-17 receptor within the metastatic lesions. Moreover, IL-17 increased the expression of CXCR2 ligands and cell proliferation of Cl66 cells. The supernatant of Cl66-Dox and Cl66-Pac cells enhanced neutrophil chemotaxis. In addition, IL-17–induced neutrophil chemotaxis was dependent on CXCR2 signaling. Collectively, these data demonstrate that the IL-17–CXCR2 axis facilitates the recruitment of neutrophils to the tumor sites, thus allowing them to play a cancer-promoting role in cancer progression.

IL-17-CXC Chemokine Receptor 2 Axis Facilitates Breast Cancer Progression by Up-Regulating Neutrophil Recruitment.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies. Desmoplasia and tumor-supporting inflammation are hallmarks of PDAC. The tumor microenvironment contributes significantly to tumor progression and spread. Cancer-associated fibroblasts (CAFs) facilitate therapy resistance and metastasis. Recent reports emphasized the concurrence of multiple subtypes of CAFs with diverse roles, fibrogenic, and secretory. C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor known for its role during inflammation and its adverse role in PDAC. Oncogenic Kras upregulates CXCR2 and its ligands and, thus, contribute to tumor proliferation and immunosuppression. CXCR2 deletion in a PDAC syngeneic mouse model produced increased fibrosis revealing a potential undescribed role of CXCR2 in CAFs. In this study, we demonstrate that the oncogenic Kras-CXCR2 axis regulates the CAFs function in PDAC and contributes to CAFs heterogeneity. We observed that oncogenic Kras and CXCR2 signaling alter CAFs, producing a secretory CAF phenotype with low fibrogenic features; and increased secretion of pro-tumor cytokines and CXCR2 ligands, utilizing the NF-κB activity. Finally, using syngeneic mouse models, we demonstrate that oncogenic Kras is associated with secretory CAFs and that CXCR2 inhibition promotes activation of fibrotic cells (myofibroblasts) and impact tumors in a mutation-dependent manner.

CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma remains one of the most challenging human cancers. Desmoplasia is predominant in this disease exhibiting a strong stromal reaction with an abundance of the cancer-associated fibroblasts (CAFs). We aimed in this study to investigate the reciprocal interaction between the tumor cells and the CAFs and its effect on tumor cells survival. We hypothesized that the survival of pancreatic cancer cell with aggressive phenotype is modulated by the Interactions between malignant pancreatic tumor cells and surrounding CAFs. To examine this, we utilized co-culture methods where tumor cells with different malignant potentials, HPAF (low) HPAF-CD11 (moderate/high) co-cultured with CAFs. CAFs-conditioned media increased the growth of HPAF-CD11 but not HPAF cells and increased CXCL8 levels highly in HPAF-CD11 and slightly in HPAF. The growth stimulatory effect and elevated CXCL8 level caused by CAFs-conditioned media were diminished by neutralizing the fibroblast growth factor-2 (FGF-2). In addition, conditioned media of HPAF-CD11 increased CAFs cell number whereas that of HPAF did not, and these effects were suppressed by neutralizing CXCL8. Furthermore, data from gene expression microarray study exhibited different expression profiles between HPAF and HPAF-CD11 when co-culture with CAFs. A significant increase in CXCL8 and FGF-2 expression was observed with HPAF-CD11/CAFs co-culture and to a lower extent with HPAF/CAFs co-culture. Together, these data demonstrate a paracrine bi-directional interaction between pancreatic tumor cells and the CAFs through CXCL8 and FGF-2 that helps the tumor growth. Future in-depth study of these pathways will assist in obtaining diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma.

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Mohammad Awaji

Papers

Tumor-Associated Neutrophils in Cancer: Going Pro.

Cancer-Associated Fibroblasts' Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma.

IL-17-CXC Chemokine Receptor 2 Axis Facilitates Breast Cancer Progression by Up-Regulating Neutrophil Recruitment.

CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.

Cancer-Associated Fibroblasts Enhance Survival and Progression of the Aggressive Pancreatic Tumor Via FGF-2 and CXCL8.