The PI3K/AKT Pathway and Renal Cell Carcinoma

Guo, Haipeng; Germán, Péter; Bai, Shanshan; Barnes, Sean; Guo, Wei; Qi, Xiangjie; Lou, Hongxiang; Liang, Jiyong; Jonasch, Eric; Mills, Gordon B.; Ding, Zhiyong

doi:10.1016/j.jgg.2015.03.003

Cited by 268 publications

(211 citation statements)

References 95 publications

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“…The PI3k/Akt/mTOR protein cascade is one of the three major signaling pathways associated with receptor tyrosine kinases that have been identified in cancer cells [32]. Inhibition of PI3K isoforms, AKT, mammalian targets of rapamycin (mTOR), and other components in the pathway are being actively pursued for targeted cancer therapy [33]. It has been demonstrated that the VHL/HIF and PI3K/AKT pathways cross-talk extensively in a large signaling network, contributing to RCC [34, 35].…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Xie

et al. 2016

Oncotarget

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Infiltrating macrophages are a key component of inflammation during tumorigenesis and progression. However, the role of macrophages in renal cell carcinoma (RCC), especially in the stage of RCC malignant progression, is still unclear. Here, we found the macrophages could be recruited more easily into RCC tissues than the surrounding non-tumor tissues. In vitro co-culture system also confirmed RCC cells had a better capacity to recruit macrophages via CXCL8 signaling than normal renal epithelial cells. The consequences of recruiting more macrophages may then increase RCC cells invasion abilities. Mechanism dissection revealed that infiltrating macrophages could function through induction of epithelial-mesenchymal transition and increased cancer stem cell-like populations via activation of AKT/mTOR signal, and then led to increasing RCC cells invasion. The orthotopically xenografted mouse model with RCC cells and macrophages also confirmed that infiltrating macrophages could increase RCC cells progression via AKT/mTOR signal. Together, our results reveal a new mechanism that macrophages in the RCC tumor microenvironment could increase RCC metastasis via activation of the AKT/mTOR signals. Targeting this newly identified signaling may help us to better inhibit RCC metastasis.

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Section: Discussionmentioning

confidence: 99%

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

Zhao

Xie

et al. 2016

Oncotarget

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“…Kidney cancer is the ninth most diagnosed cancer in the world . ccRCC, the most frequent kidney cancer, is associated with biallelic inactivation of the tumor suppressor gene VHL .…”

mentioning

confidence: 99%

Quantitative proteomics to study a small molecule targeting the loss of von Hippel–Lindau in renal cell carcinomas

Bouhamdani

Joy

Barnett

et al. 2017

Intl Journal of Cancer

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Inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), is known to play an important role in the development of sporadic clear cell renal cell carcinomas (ccRCCs). Even if available targeted therapies for metastatic RCCs (mRCCs) have helped to improve progression-free survival rates, they have no durable clinical response. We have previously shown the feasibility of specifically targeting the loss of VHL with the identification of a small molecule, STF-62247. Understanding its functionality is crucial for developing durable personalized therapeutic agents differing from those available targeting hypoxia inducible factor (HIF-) pathways. By using SILAC proteomics, we identified 755 deregulated proteins in response to STF-62247 that were further analyzed by ingenuity pathway analysis (IPA). Bioinformatics analyses predicted alterations in 37 signaling pathways in VHL-null cells in response to treatment. Validation of some altered pathways shows that STF-62247's selectivity is linked to an important inhibition of mTORC1 activation in VHL-null cells leading to protein synthesis arrest, a mechanism differing from two allosteric inhibitors Rapamycin and Everolimus. Altogether, our study identified signaling cascades driving STF-62247 response and brings further knowledge for this molecule that shows selectivity for the loss of VHL. The use of a global SILAC approach was successful in identifying novel affected signaling pathways that could be exploited for the development of new personalized therapeutic strategies to target VHL-inactivated RCCs.

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“…In addition to these epigenetic regulators, many other gene mutations and somatic copy number aberrations (SCNA) have been associated with ccRCC. Alterations in PTEN , PI3Kca and mTOR are also prevalent in ccRCC, which are all key players in the PI3k–AKT–mTOR pathway regulating cell proliferation and HIF stabilisation . With regard to SCNA in ccRCC, 5q gains are the second most frequent alterations following 3p deletions with the SQSTM1 gene, thought to be the pathogenic target for this gain .…”

Section: Ccrcc Beyond Vhlmentioning

confidence: 99%

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

2018

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The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.

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The PI3K/AKT Pathway and Renal Cell Carcinoma

Cited by 268 publications

References 95 publications

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

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

Quantitative proteomics to study a small molecule targeting the loss of von Hippel–Lindau in renal cell carcinomas

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

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