Tumor‐associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer

Tauchi, Yukie; Tanaka, Hiroaki; Kumamoto, Kenzo; Tokumoto, Mao; Sakimura, Chie; Sakurai, Katsunobu; Kimura, Kenjiro; Toyokawa, Takahiro; Amano, Ryosuke; Kubo, Naoshi; Muguruma, Kazuya; Yashiro, Masakazu; Maeda, Kiyoshi; Ohira, Masaichi; Hirakawa, Kosei

doi:10.1111/cas.12977

Cited by 25 publications

(19 citation statements)

References 40 publications

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“…It has been well-established that TAMs play a pivotal role in tumor progression and invasion by up-regulating MMPs 34 , 35 . The canonical activation of PAR1, the first identified thrombin receptor 36 , is induced by thrombin.…”

Section: Discussionmentioning

confidence: 99%

MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells

Huang

Guo

et al. 2018

Theranostics

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The molecular mechanism of perineural invasion (PNI) is unclear, and insufficient detection during early-stage PNI in vivo hampers its investigation. We aimed to identify a cytokine paracrine loop between pancreatic ductal adenocarcinoma (PDAC) cells and nerves and established a noninvasive method to monitor PNI in vivo.Methods: A Matrigel/ dorsal root ganglia (DRG) system was used to observe PNI in vitro, and a murine sciatic nerve invasion model was established to examine PNI in vivo. PNI was assessed by MRI with iron oxide nanoparticle labeling. We searched publicly available datasets as well as obtained PDAC tissues from 30 patients to examine MMP1 expression in human tumor and non-tumor tissues.Results: Our results showed that matrix metalloproteinase-1 (MMP1) activated AKT and induced protease-activated receptor-1 (PAR1)-expressing DRG to release substance P (SP), which, in turn, activated neurokinin 1 receptor (NK1R)-expressing PDAC cells and enhanced cellular migration, invasion, and PNI via SP/NK1R/ERK. In animals, hind limb paralysis and a decreased hind paw width were observed approximately 20 days after inoculation of cancer cells in the perineurium. MMP1 silencing with shRNA or treatment with either a PAR1 or an NK1R antagonist inhibited PNI. MRI detected PNI as early as 10 days after implantation of PDAC cells. PNI also induced PDAC liver metastasis. Bioinformatic analyses and pathological studies on patient tissues corroborated the clinical relevance of these findings.Conclusion: In this study, we provided evidence that the MMP1/PAR1/SP/NK1R paracrine loop contributes to PNI during the early stage of primary tumor formation. Furthermore, we established a sensitive and non-invasive method to detect nerve invasion using iron oxide nanoparticles and MRI.

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Section: Discussionmentioning

confidence: 99%

MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells

Huang

Guo

et al. 2018

Theranostics

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“…It can be favored by various humoral factors released by different cellular components, directly or indirectly correlated with the tumor growth. Here, paracrine action can be considered [16][17][18][19][20][21]. The methodology of our study is rather not complete.…”

Section: Discussionmentioning

confidence: 99%

Deep inside of gastric signet-ring cell carcinoma

Roncati¹,

Manenti²,

Barbolini³

et al. 2018

neo

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The histology of signet-ring cell carcinoma (SRC) of the stomach has been revisited with the support of current immuno- histochemical techniques in order to explain particular features of this tumor; its great capacity of local diffusion and lymph node metastasis, also through a neo-lymphoangiogenesis. An observational retrospective study on 50 cases of SRC in stage II and III has been performed with the addition of histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange) and immunohistochemical (cytocheratin, CD3, CD4, CD8, CD10, CD56, CD68, perforin, granzyme B, podoplanin, collagen type IV) investigations for each case. The signet ring cells, typical for this tumor, show abundant content of electro-negative sialomucins and demonstrate a great capacity of diffusion through the gastric wall. They evoke production and deposition of collagen type IV in the sub-mucosa layer through the local action of fibroblasts. The immunological response to this tumor in the gastric wall and in the metastatic lymph nodes is represented by an increase of B and T-helper lymphocytes, but not of T-killers or natural killers. The neoplastic cells are curiously able to avoid these newly formed 'lymph nodules'. An extended neo-lymphangiogenesis has been observed around the primary tumor and in metastatic lymph nodes. A careful immunohistochemical characterization has allowed a better knowledge of SRC, regarding especially the peculiar behavior of local diffusion of its cells, the associated neo-lymph angiogenesis, and poor immunological reaction.

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“…Macrophages induce the capillary formation of lymphatic endothelial cells. Co-culture with GC pretreated macrophages upregulate lymphangiogenic factors, including inflammatory cytokines, MMPs, adhesion molecules and vascular endothelial growth factor-C. Interaction between lymphatic endothelial cells and macrophages may be an important initial step in tumor lymphangiogenesis developing lymph node metastasis [42] . The high density of CD163+ TAMs (M2 macrophage) is an independent prognostic marker heralding prolonged disease-free survival.…”

Section: Tumor-associated Macrophagesmentioning

confidence: 99%

Microenvironment in the pathogenesis of gastric cancer metastasis

Shinmoto¹,

Ishimoto²,

Baba³

2018

JCMT

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Tumor tissues contain cancer cells, other cellular and non-cellular components. Tumor microenvironments consist of cancer cells and various types of stromal cells, cancer associated fibroblasts, bone marrow-derived cells, endothelial cells, and hematopoietic cells, mainly tumor-associated macrophages and tumor-infiltrating lymphocytes. Increasing recent evidence has demonstrated that alteration of tumor microenvironments is deeply implicated in tumor progression and metastasis in gastric cancer (GC) patients. Recent investigations have provided insights into the molecular mechanisms of the interaction between tumor cells and tumor microenvironments. Interactions between cancer cells and their microenvironment with cytokines and microRNA in extracellular vesicles, such as the exosome, can have a substantial impact on tumor characteristics. Alterations in the tumor microenvironment may play a crucial role in facilitating the progression of tumor cells and metastasis, as well as the activation of cell signaling pathways, which are associated with GC cell proliferation and invasion by genetic or epigenetic alterations. In this review, significant molecular insights into the tumor microenvironment, which consist of cancer associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages and tumor-infiltrating lymphocytes; the interactions between cancer cells and their microenvironment; and the clinical impacts of alterations of GC microenvironments will be discussed.

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Tumor‐associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer

Cited by 25 publications

References 40 publications

MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells

MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells

Deep inside of gastric signet-ring cell carcinoma

Microenvironment in the pathogenesis of gastric cancer metastasis

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