Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

Chappell, John C.; Payne, Laura Beth; Rathmell, W. Kimryn

doi:10.1172/jci120855

Cited by 76 publications

(52 citation statements)

References 200 publications

(196 reference statements)

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“…As many phenomena in hypoxia could be explained by HIF1A, hypoxia‐independent activation of HIF1A signaling could mimic many hypoxia‐mediated phenomena, even in the normoxia condition. Thus, these mechanisms underlying oxygen‐independent activation of HIF1A signaling are now termed pseudohypoxia . From this perspective, we describe an overview of pseudohypoxia in cancer and recent findings.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

et al. 2019

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Since the first identification of hypoxic cells in sections of carcinomas in the 1950s, hypoxia has been known as a central hallmark of cancer cells and their microenvironment. Indeed, hypoxia benefits cancer cells in their growth, survival, and metastasis. The historical discovery of hypoxia‐inducible factor‐1α ( HIF 1A) in the early 1990s had a great influence on the field as many phenomena in hypoxia could be explained by HIF 1A. However, not all regions or types of tumors are necessarily hypoxic. Thus, it is difficult to explain whole cancer pathobiology by hypoxia, especially in the early stage of cancer. Upregulation of glucose metabolism in cancer cells has been well known. Oxygen‐independent glycolysis is activated in cancer cells even in the normoxia condition, which is known as the Warburg effect. Accumulating evidence and recent advances in cancer metabolism research suggest that hypoxia‐independent mechanisms for HIF signaling activation is a hallmark for cancer. There are various mechanisms that generate pseudohypoxic conditions, even in normoxia. Given the importance of HIF 1A for cancer pathobiology, the pseudohypoxia concept could shed light on the longstanding mystery of the Warburg effect and accelerate better understanding of the diverse phenomena seen in a variety of cancers.

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Section: Introductionmentioning

confidence: 99%

“…Thus, these mechanisms underlying oxygen-independent activation of HIF1A signaling are now termed pseudohypoxia. [10][11][12][13] From this perspective, we describe an overview of pseudohypoxia in cancer and recent findings.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

et al. 2019

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“…Among the top 100 target genes, several are associated with RCC. For example, 2 potential targets, von Hippel‐Lindau ( VHL ) and chromodomain helicase DNA binding protein 5 ( CHD5 ), function as tumor suppressors in RCC . Among others, high‐mobility group AT‐hook 2 ( HMGA2 ) facilitates the epithelial‐mesenchymal transition of RCC cells and Ras‐related protein RAB22A accelerates RCC cell proliferation and invasion .…”

Section: Discussionmentioning

confidence: 99%

“…The MiT family proteins, including TFE3, activate transcription of targets through the E‐box consensus motif CANNTG, as do TFE3 fusion proteins . Numerous transcription factors reportedly bind E‐boxes and some, such as myc and hypoxia‐inducible factor, are activated in human RCC cells . These factors might also contribute to expression of both miR‐204‐5p and TRPM3 in Xp11 tRCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, 2 potential targets, von Hippel-Lindau (VHL) and chromodomain helicase DNA binding protein 5 (CHD5), function as tumor suppressors in RCC. 34,35 Among others, high-mobility group AT-hook 2 (HMGA2) facilitates the epithelial-mesenchymal transition of RCC cells 36 and Ras-related protein RAB22A accelerates RCC cell proliferation and invasion. 37 Thus, miR-204-5p-mediated inhibition of tumor suppressors might underlie the development and progression of Xp11 tRCC, although these mechanisms should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐204‐5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma

Kurahashi

Kadomatsu

et al. 2019

Cancer Science

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Xp11.2 translocation renal cell carcinoma (Xp11 tRCC ) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE 3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early‐stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC ‐ TFE 3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)‐204‐5p levels in urinary exosomes of 40‐week‐old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA‐204‐5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR‐204‐5p‐containing exosomes. Notably, we also observed increased miR‐204‐5p levels in urinary exosomes in 20‐week‐old renal PRCC ‐ TFE 3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40‐week‐old Tg mice, suggesting that miR‐204‐5p increases follow expression of constitutively active TFE 3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR‐204‐5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC ‐ TFE 3 fusion gene. These findings suggest that miR‐204‐5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC .

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Single‐Cell RNA‐Sequencing‐Aided Covalent Organic Frameworks‐Based Microneedle Design Targeting Phototherapy Resistant Tumor Cell

Zhang,

Wang

et al. 2024

Adv Funct Materials

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Covalent organic frameworks (COFs) exhibit immense potential for phototherapy due to their exceptional light absorption, photostability, and biocompatibility. Nevertheless, tumor cells can develop resistance to phototherapy after an initial response, posing a significant challenge for complete eradication. In this study, a COF‐based photosensitizer, TCN‐PPDA‐COF, is designed with outstanding photothermal properties and delivered to tumors using microneedles (MN) to enhance cancer phototherapy. Single‐cell RNA‐sequencing (scRNA‐seq) technology is then utilized to explore the mechanisms underlying tumor cell adaptation to COF‐mediated phototherapy. The scRNA‐seq analysis revealed that phototherapy‐resistant tumor cells displayed elevated expression of HIF‐1α and VEGF signaling pathways, fostering intratumoral angiogenesis and facilitating their continued survival during phototherapy. In response to this phenomenon, a unique CA‐microneedle (MN) patch is developed, tailored for co‐delivering TCN‐PPDA‐COF and angiogenesis inhibitors AL3818 to the tumor site. The CA‐MN patches can effectively inhibit angiogenesis in tumors while mediating phototherapy, thereby obliterating the phototherapy‐resistant tumor cells. In 4T1 tumor‐bearing mouse model, the CA‐MN patches achieved nearly complete regression of tumor grafts and activated host anti‐tumor immunity, thereby enhancing the response rate of αPD‐1 and effectively restraining tumor metastasis and recurrence. This study underscored an ingenious approach to modify COF‐MN patches through scRNA‐seq technology.

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Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

Cited by 76 publications

References 200 publications

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

MicroRNA‐204‐5p: A novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma

Single‐Cell RNA‐Sequencing‐Aided Covalent Organic Frameworks‐Based Microneedle Design Targeting Phototherapy Resistant Tumor Cell

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