Inflammation and Cancer: Triggers, Mechanisms, and Consequences

Emerging Role of Semaphorins as Major Regulatory Signals and Potential Therapeutic Targets in Cancer

Tumor microenvironment in cancer treatment and metastasis

The role of opioids in cancer progression.

Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.

Expression of Cathepsin D in Colorectal Adenocarcinomas: Correlation with Clinicopathologic Features

Inflammation plays an important role to the development of cancer and promotes all stages of tumorigenesis. Cancer cells, as well as inflammatory cells, carry out reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cancer cells within the TME are highly able to change their phenotypic and functional characteristics. Here, we review the relationship between inflammation and infection in cancer origins, and the mechanisms whereby inflammation and infection drive tumor formation. We discuss how infection promotes tumorigenesis related to inflammatory processes typically found in autoimmune diseases, release of inflammatory mediators induced by tumors, inflammation induced by therapy in cancer, and stimuli for induction of inflammation during tumorigenesis, including spatiotemporal considerations. A better understanding of the fundamental rules of engagement that govern the molecular and cellular mechanisms of tumor-promoting inflammation will be essential for further development of cancer therapies.

SY40-03: The FAP+ stromal cell: Cancer-induced immune suppression and cachexia

Stress‐sensing toll‐like receptor as a driver of angiogenesis

Traditional cancer therapies, including surgery, radiation, and chemotherapy, have long been the cornerstone in treating malignant tumors. However, with advancements in science and technology, novel cancer treatment modalities such as immunotherapy, targeted therapy, sonodynamic therapy, and photodynamic therapy have emerged, revolutionizing the therapeutic landscape. These innovative approaches not only transform the paradigms of tumor treatment but also significantly impact the stromal cells within the tumor immune microenvironment. Stromal cells, which are crucial components of the tumor microenvironment, include fibroblasts, endothelial cells, cancer stem cells and immune cells. These cells play pivotal roles in the initiation, progression, and metastasis of tumors. New therapeutic methods exert their effects on stromal cells through various mechanisms. For example, immunotherapy activates the patient's own immune system, enabling immune cells to more effectively recognize and attack tumor cells while also altering the functions of tumor-associated fibroblasts, thus reshaping the tumor microenvironment. Sonodynamic and photodynamic therapies utilize specific wavelengths of sound and light waves to activate particular drugs within tumor cells, and then generate reactive oxygen species that kill the cancer cells. These methods also affect stromal cells by disrupting their interactions with tumor cells, thereby further inhibiting tumor growth and spread. Therefore, novel cancer treatments target not only tumor cells directly but also modulate stromal cells in the tumor microenvironment through multiple pathways, to achieve more effective anti-tumor outcomes. The application of these new therapies heralds a new era in cancer treatment and offers patients greater hope and possibilities. This research topic collection entitled "impact of emerging treatment modalities on stromal cells in the tumor microenvironment", compiled work by authors from various research teams.The first paper of the collection was a review. Overcoming resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) remains a formidable obstacle in the treatment landscape. The resistance mechanisms are complex and multifaceted, involving alterations in molecular targets, activation of alternative signaling pathways, tumor heterogeneity, changes within the tumor microenvironment, immune evasion, and immunosuppression. Addressing these challenges requires a multi-pronged approach, including the development of combination therapies, a deeper understanding of resistance mechanisms to optimize the use of new drug targets, identification of relevant biomarkers, and modulation of the tumor microenvironment. In this review, Xiang et al., provide an overview of the diverse mechanisms contributing to resistance in NSCLC and explore the latest promising strategies aimed at overcoming these challenges to enhance treatment efficacy for NSCLC patients.The second paper of the collection was also a review related to pre-metastatic niches (PMNs) (Li et al.). Evidence indicates that extracellular vesicles (EVs) secreted by cancer cells play a critical role in orchestrating the development of PMNs. These tumor-derived EVs facilitate bidirectional communication between cancerous and stromal cells within both local and distant microenvironments. The EVs, which contain mRNAs, small RNAs, microRNAs, DNA fragments, proteins, and metabolites, influence metastatic organotropism, promote angiogenesis, alter stromal cell phenotypes, remodel the extracellular matrix, induce immunosuppression, and modify the metabolic landscape of organs. This review offers an in-depth analysis of PMNs formation and the mechanisms driven by EVs, along with potential strategies to inhibit cancer metastasis by targeting the formation of PMNs.The third study focused on the role of monocytes in the tumor microenvironment to inform targeted cancer therapies (Li et al.). Using an innovative method with four 20color flow cytometry panels, researchers conducted a comprehensive analysis of peripheral immune cells, especially monocyte subsets. Advanced techniques such as tSNE and FlowSom were used to profile 50 cell surface markers related to immunological functions. The results enhance the identification of monocyte subsets, aiding the development of personalized immunotherapies and improving diagnostic accuracy. Key discoveries include distinct marker expression patterns associated with tumor progression, offering new targets for therapeutic intervention.The last study was a retrospective study that investigated the relationship between smoking history and the effectiveness of immune checkpoint inhibitors (ICIs) in bladder cancer patients (Kong et al.). Analyzing data from 348 patients, including a validation cohort of 248, the study examines smoking history, clinical characteristics, and immune profiles. While no significant differences in overall survival were found among current, former, and never smokers, former smokers exhibited a trend toward better immunotherapy responses. Additionally, PD-L1 expression was higher in former smokers. These findings suggest that smoking history may influence tumor response to ICIs, emphasizing the need to consider lifestyle factors in personalized cancer treatment strategies.In conclusion, this collection of papers stresses the importance of stromal cells in the tumor microenvironment for cancer treatments. Key studies include overcoming resistance in NSCLC, the role of extracellular vesicles in pre-metastatic niche formation, monocyte profiling for personalized immunotherapies, and the influence of smoking history on immune checkpoint inhibitor effectiveness in bladder cancer. These advancements hold promise for more effective and personalized cancer treatments, highlighting the need for further exploration of the tumor microenvironment and patient-specific factors.

GENERAL COMMENTARY article Front. Oncol., 28 May 2015Sec. Molecular and Cellular Oncology Volume 5 - 2015 | https://doi.org/10.3389/fonc.2015.00118

Tumor behavior is not entirely determined by tumor cells. Studies have demonstrated that a variety of non-tumor cells in the tumor microenvironment affect tumor behavior; thus, a new focus of cancer research has been the development of novel cancer treatment ideas and therapeutic targets based on the effects of these cells. Mesenchymal stem cells (MSCs) are an important component of the tumor microenvironment; however, previous studies have produced controversial results regarding whether MSCs promote or inhibit tumor growth and progression. In particular, Naïve MSCs and tumor-derived MSCs (T-MSCs) have different functions. Naïve MSCs could exert bidirectional effects on tumors because these cells can both promote and inhibit tumor progression while T-MSCs promote tumor progression due to influences from the tumor itself and from the inflammatory tumor microenvironment. As an unhealed wound, tumor produces a continuous source of inflammatory mediators and causes aggregation of numerous inflammatory cells, which constitute an inflammatory microenvironment. Inflammatory factors can induce homing of circulating MSCs and MSCs in adjacent tissues into tumors, which are then being “educated” by the tumor microenvironment to support tumor growth. T-MSCs could recruit more immune cells into the tumor microenvironment, increase the proportion of cancer stem cells and promote tumor angiogenesis, further supporting tumor progression. However, as plasticity is a fundamental feature of MSCs, MSCs can also inhibit tumors by activating various MSC-based signaling pathways. Studies of the mechanisms by which interactions among tumors, MSCs, and the inflammatory microenvironment occur and methods to disrupt these interactions will likely reveal new targets for cancer therapy.

Tumors are composed of both cancer cells and host cells including stromal cells (e.g., fibroblasts and mesenchymal cells), vascular endothelial cells, and immune/inflammatory cells (e.g., macrophages, monocytes, neutrophils and lymphocytes). The growth, invasiveness and metastatic potential of cancer cells are influenced by various neighboring cells that comprise the so-called tumor microenvironment. Therefore, the precise understanding of interaction and communication between cancer cells and surrounding environment is very essential for the discovery of novel anticancer targets and development of efficient therapeutic and preventive strategies. The concept that the microenvironment of developing tumor is a crucial regulator of carcinogenesis was originally proposed by Paget in his famous ‘seed-and-soil’ hypothesis. During carcinogenesis, there might be molecular lesions in cells of the microenvironment and in epithelial cells themselves. It is hence necessary to consider the microenvironment of cancer and its associated epithelium as a whole. Recently much attention has focused on tumor microenvironment as an integral and essential part of developing innovative new cancer therapeutic and preventive regimes. The success of chemo-/radiotherapy as well as chemoprevention depends more fundamentally on their comprehensive modulation of the tumor microenvironment. There is mounting evidence from preclinical and clinical studies that persistent inflammation functions as a driving force in the journey to cancer. While inflammation stimulates development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Some proinflammatory mediators can turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will accelerates tumor angiogenesis, metastasis and invasion. In this context, the use of anti-inflammatory and proresolving agents to control the function and behavior of cells in the inflammatory microenvironment will be an important approach to the overall control of cancer. Supported by the Global Core Research Center grant from the National Research Foundation, Republic of Korea.

Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME's active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME.

Modulating the activation of hepatic stellate cells: a cunning way for metastatic cells to create a permissive soil for seeding in the liver?

The Hallmarks of Cancer provided a framework that has guided cancer research since it was first published. Although Hanahan and Weinberg highlighted the role of the tumor microenvironment, the existing hallmarks should be expanded to include another crucial aspect of the tumor microenvironment—the tumor-neural interaction. Traditionally, the nervous and immune systems have been viewed as functionally and anatomically distinct, even though they share a critical common task: to detect and respond to internal and external threats, whether physical, chemical, or biological. While the role of the immune system is well established in cancer, and both immune evasion and tumor-promoting inflammation are considered hallmarks of cancer, the nervous system is typically viewed as a tissue affected by cancer and as a conduit for the transmission of cancer-related pain and perineural invasion. Recent work by us and others has shown that the nervous system plays several important roles in promoting tumor initiation, progression, and metastasis. By comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We showed that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumor growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents one mechanism by which tumor-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumor progression and is a potential target for anticancer therapy. These studies suggest that newly formed nerve fibers support both cancer cells and the tumor microenvironment. However, despite increasing recognition of tumor-associated neurogenesis—the formation of new nerve fibers—this topic has been relatively understudied. In the last decade, emerging technologies have enabled us to bridge the gaps between cancer research and neuroscience and to take a glimpse into the roles of nerves and their supporting cells like Schwann cells, in cancer. Specifically, the development of spatial imaging and in vivo neural tracing and recording techniques removed some of the obstacles that impeded cancer neuroscience research, namely, our ability to capture phenotypes and functions in the tumor microenvironment (i.e., dendrites and axons, far away from the neuron cell body or soma) using high-dimensional labeling techniques (e.g., mass cytometry and multiplex immunofluorescence). Using these techniques, it has been shown that in many types of cancer, ablation of different portions of the nervous system prevents cancer development and progression. This process is similar to another microenvironmental hallmark of cancer—tumor angiogenesis, whereby tumors induce the growth of new blood vessels to supply them with oxygen and blood-borne nutrients. Importantly, neuromodulation with both genetic and pharmacologic approaches has been shown to affect not only tumor growth but also the antitumor immune response. Neurogenesis should be recognized as a hallmark of cancer for two important reasons. First, doing so would establish the neo-neurogenic process as a highly relevant therapeutic target for both the prevention and treatment of cancer. Second, it would foster interdisciplinary crosstalk between two fields that traditionally have progressed along parallel paths. We have credentialed the neoneurogenic process as a highly relevant therapeutic target for both the prevention and treatment of cancer; hopefully, in the next decade we will see more clinical trials targeting the neural microenvironment of cancer aiming to prevent tumor’s development and progression and improve patient’s quality of life. Citation Format: Moran Amit. Neural regulation of tumors and their microenvironment: Novel, actionable, hallmark of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY12-02.