Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.

The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.

The protein known as Spred1 (Sprouty‐related Ena/VASP homology‐1 domain‐containing protein) has been identified as a negative regulator of growth factor‐induced ERK/mitogen‐activated protein kinase activation. Spred1 has also been implicated as the target of microRNA‐126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down‐regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up‐regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcεRI‐mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell‐specific Spred1‐conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1‐deficient bone marrow‐derived mast cells were highly activated by cross‐linking of Fcε‐R stimulation as well as by IL‐3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126.

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.

The IL6 family of cytokines, including IL6 and leukemia-inhibitory factor (LIF), are induced during inflammation and are also expressed in many types of cancer where they play an important role in tumor development. IL6 family cytokines mainly activate the JAK–STAT3 pathway via the coreceptor, gp130, and IL6 is known to activate the Src family kinase (SFK)–Yes-associated protein (YAP) pathway. The current study investigated the role of autocrine LIF in human esophageal squamous cell carcinoma (ESCC) that highly expresses LIF. LIF knockdown had various effects on cancer cells, including profound changes in gene expression, suppression of cell proliferation, migration/invasion and sphere formation, and induction of apoptosis. Similar to IL6, LIF activated the SFK–YAP pathway as well as the JAK–STAT3 pathway. LIF-induced YAP activation was more important for cancer cell proliferation than LIF-induced STAT3 activation, and concomitant YAP and STAT3 activation completely compensated for the role of LIF in human ESCC growth. We also confirmed that SFK activation and LIF expression were correlated with YAP activation in human ESCC clinical samples. Furthermore, simultaneous inhibition of the SFK–YAP and JAK–STAT3 pathways in human ESCC cells was more effective at suppressing cell proliferation than single inhibition, and autocrine LIF signaling promoted human ESCC growth in vivo. Therefore, the LIF–SFK–YAP axis may represent a new therapeutic target for human ESCC. Implications: Autocrine LIF signaling promotes human ESCC progression via SFK-dependent YAP activation and is a new potential target of treatment for human ESCC.

Background/Objectives: Endometrial cancer is one of the most common gynecological malignancies, with increasing incidence and mortality rates, particularly in developed countries. L1 cell adhesion molecule (L1CAM) has been identified as a poor prognostic factor for human endometrial cancer; however, the molecular mechanisms underlying its role in tumor progression remain unclear. Methods: We investigated the biological significance of L1CAM in human endometrial cancer using multiple cell lines. Functional analyses, including cell proliferation, cell cycle, and apoptosis assays, were performed after L1CAM knockdown or overexpression. Results: L1CAM promoted the transition of endometrial cancer cells from the G0/G1 phase and enhanced cell proliferation. L1CAM knockdown inhibited NF-κB signaling by reducing NF-κB (p65) phosphorylation and downregulating the expression of downstream targets such as TNF. Overexpression of constitutively active IKKβ restored the proliferation defect caused by L1CAM knockdown, supporting the role of NF-κB as a key downstream effector of L1CAM. Immunohistochemical analysis revealed a significant correlation between L1CAM expression and nuclear NF-κB (p65) positivity rates in human patient samples. Furthermore, combination therapy with cisplatin and an IKK inhibitor enhanced the anti-proliferative effect. Conclusions: Our study demonstrated that L1CAM promotes proliferation and chemotherapy resistance in human endometrial cancer through activation of the NF-κB signaling pathway. Therapeutic strategies targeting the L1CAM-NF-κB pathway may represent a promising treatment option for improving prognosis in L1CAM-positive human endometrial cancer.