A Signaling View into the Inflammatory Tumor Microenvironment

Abstract

The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment

“…The tumor cell microenvironment (TME) is a heterogenous body constituted of tumor cells, normal resident cells, infiltrating immune cells, extracellular matrix, and a variety of secreted mediators ( 31 – 34 , 41 , 42 ). The normal cells of the TME help in tumor promotion, and the intercellular communication inside the TME is mediated through the interwoven complex network involving various cytokines and enzymes, along with a plethora of growth factors ( 43 – 47 ).…”

“…As reviewed in the previous section, the role of various signaling pathways in the alternation of the TME especially cytokine-mediated signaling is crucial and these alternations result in the hypoxic condition and acidic environment in the TME, which is the hallmark of any cancer ( 11 , 18 ). To overcome this hostile microenvironment, the TME normalizes oxygen level and ensures adequate nutrient supply by promoting angiogenesis through co-ordination between its various intrinsic and extrinsic factors ( 33 , 34 ). The upregulation of aerobic glycolysis in cancer cells is one example of an intrinsic factor that resulted in the “Warburg effect”.…”

“…This increased level of lactate, in turn, alters the extrinsic factors resulting in alteration in the extracellular matrix (ECM) and angiogenesis along with tumor invasion ( 18 ). It has been shown that oncogenes like C-Myc, KRAS, and PI3K regulated the uplifting of glycolysis rate by upregulating the expression of various proteins of the glycolytic pathway ( 32 – 34 ).…”

“…Various reports associated the different genetic alternations in genes related to cytokine signaling with the pathogenesis of TCLs ( 25 – 30 ). Interactions between lymphoma cells and their microenvironment mediated by the altered cytokine profile of the tumor microenvironment (TME) disturb tissue homeostasis and thus favor lymphoma development and progression ( 31 – 34 ). The various aspects of T-cell lymphoma development like metastasis, migration, invasion apoptosis, and epithelial–mesenchymal transition (EMT) are regulated by the altered metabolic phenotype of T lymphoma cells and their abnormal interaction with other non-neoplastic cellular components of the TME ( 22 , 24 , 31 ).…”

Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells

“…A major molecular connection between cancer and inflammation resides in chemokines, soluble factors released by immune cells to regulate their response, which also stimulate the proliferation or survival of most human neoplastic cell types, including colorectal cells [12][13][14][15][16]. In contrast, the genetic alterations selected in cancer cells lead to the secretion of factors that stimulate stromal cells and propagate the inflammatory microenvironment.…”