Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations <i>via</i> AKT and mTOR signaling

Zhao, Yang; Xie, Hongjun; He, Dalin; Li, Lei

doi:10.18632/oncotarget.9873

Cited by 52 publications

(38 citation statements)

References 37 publications

(36 reference statements)

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“…47 For several types of malignancies, primarily carcinomas, mTOR activity is higher in metastases than in the primary tumour site and is typically associated with a poorer prognosis. 51,52 Our study implicates a novel signalling axis between mTOR and proteolytic activity with implications for the microarchitecture of the immune system. 51,52 Our study implicates a novel signalling axis between mTOR and proteolytic activity with implications for the microarchitecture of the immune system.…”

Section: Discussionmentioning

confidence: 85%

“…[48][49][50] The connection between mTOR and metastatic potential has been mostly attributed to promoting endothelial to mesenchymal transition and allowing the cells to better sustain various stress conditions, such as hypoxia or nutrient starvation. 51,52 Our study implicates a novel signalling axis between mTOR and proteolytic activity with implications for the microarchitecture of the immune system.…”

Section: Discussionmentioning

confidence: 85%

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mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

et al. 2018

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Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood-borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1 ) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underlying mechanisms for MZ B-cell loss, we have analysed the spleen MZ architecture of TSC1 mice and found it to be severely impaired. Examination of lymphotoxins (LTα and LTβ) and lymphotoxin receptor (LTβR) expression indicated that LTβR levels in spleen stroma were reduced by TSC1 deletion in the B cells. Furthermore, LTα transcripts in B cells were reduced. Because LTβR is sensitive to proteolysis, we analysed cathepsin activity in TSC1 . A higher cathepsin activity, particularly of cathepsin B, was observed, which was reduced by mTORC1 inhibition with rapamycin in vivo. Remarkably, in vivo administration of a pan-cathepsin inhibitor restored LTβR expression, LTα mRNA levels and the MZ architecture. Our data identify a novel connection, although not elucidated at the molecular level, between mTORC1 and cathepsin activity in a manner relevant to MZ dynamics.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

et al. 2018

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“…Cytokines secreted by macrophages affect the proliferation, tumorigenic transformation, or apoptosis of CSCs through various signaling pathways. 458 TAMs are closely related to CSCs or stem cell transformation. Renal epithelial cells cocultured with macrophages induce the EMT to transform renal cancer cells into CSCs expressing CD117, Nanog, and CD133.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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“…Indeed, the release of proinflammatory cytokines TNF-α by TAMs triggers the expansion of a group of stem-like cancer cells through the NF-κB pathway in a colon cancer model while TAM-derived IL-6 promotes CSCs growth via Stat3 signaling in human hepatocellular carcinoma [38,39]. Akt/mTOR signaling in clear cell renal cell carcinoma was also found to increase EMT and stem cell-like populations under the influence of TAMs [40]. Additionally, juxtacrine signaling between CSCs and TAMs through the CD90 and Eph4A receptors activate Src and NF-κB in carcinoma cells to sustain the CSC niche in breast cancer [41].…”

Section: Cancer Cell Stemness and Resistance To Therapymentioning

confidence: 99%

Tumor-Associated Macrophages: Implications in Cancer Immunotherapy

2017

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Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.

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Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations via AKT and mTOR signaling

Cited by 52 publications

References 37 publications

mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

Targeting cancer stem cell pathways for cancer therapy

Tumor-Associated Macrophages: Implications in Cancer Immunotherapy

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