Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion

Li, Fengkai; Kitajima, Shunsuke; Kohno, Susumu; Yoshida, Akiyo; Tange, Shoichiro; Sasaki, Soichiro; Okada, Nobuhiro; Nishimoto, Yuuki; Muranaka, Hayato; Nagatani, Naoko; Suzuki, Misa; Masuda, Sayuri; Thai, Tran C.; Nishiuchi, Takumi; Tanaka, Tomoaki; Barbie, David A.; Mukaida, Naofumi; Takahashi, Chiaki

doi:10.1158/0008-5472.can-18-3604

Cited by 72 publications

(48 citation statements)

References 45 publications

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“…We once established a 'soft tissue sarcoma system', derived from a well-differentiated leiomyosarcoma developed in a Trp53-null mouse, in which additional Rb inactivation induces a phenotypic change to undifferentiated type. We identified significant upregulation of CCL2 and a pro-angiogenic cytokine Vegfα following Rb depletion in this system [81]. Interestingly, mouse soft tissue sarcoma cells did not express CCR2.…”

Section: Rb Impacts the Tumor Microenvironment Via Chemokinementioning

confidence: 76%

Tumor Milieu Controlled by RB Tumor Suppressor

Kitajima

Takahashi

2020

IJMS

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The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.

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Section: Rb Impacts the Tumor Microenvironment Via Chemokinementioning

confidence: 76%

Tumor Milieu Controlled by RB Tumor Suppressor

Kitajima

Takahashi

2020

IJMS

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“…The role of pRb in immunity has been well described [31,32], with recent studies demonstrating that pRb inactivation recruits tumor-associated macrophages and immunosuppressive myeloid-derived suppressor cells within the tumor microenvironment (TME) [33]. This was found to be due to increased cytokine/chemokine secretion through altered AMP-activated protein kinase signaling from increased fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 97%

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

Conroy

Dougherty

Kruer

et al. 2020

Cancers

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Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors.

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“…It was accepted that the TAMs in cancer contribute to tumor progression by enhancing the capacity of tumor invasion, metastasis, drug-resistance, angiogenesis, as well as immune escape (17)(18)(19)(20) . MicroRNAs (miRNAs) are single-stranded RNA molecules that mediated gene expression at posttranscriptional level in various processes.…”

Section: Discussionmentioning

confidence: 99%

M2 macrophages contribute to cell proliferation and migration of breast cancer

Dou

Wang

et al. 2020

Preprint

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Background: Breast cancer is a kind of malignant tumor that severely threatens women’s health and life worldwide. Macrophages have been reported to mediate tumor progression, while the potential mechanism still needs further identification.Methods: Human monocytic cell line THP-1 was used to induce M2-macrophage. Real-time PCR and western blot were performed to determine gene expression in mRNA and protein level, respectively. Cell proliferation was determined using MTT assays, while cell migration was detected based on the scratch wound healing assays.Results: The supernatant medium of M2-macrophages incubated breast cancer cells showed increased cell proliferation and reduced expression of IRF-7. Overexpression of IRF-7 reversed the increased level of M2-macrophage induced cell proliferation and migration. The supernatant medium of M2-macrophages incubation promoted miR-1587 expression in breast cancer cells. miR-1587 overexpression promoted cell proliferation and migration of breast cancer. In addition, miR-1587 knockdown suppressed cell proliferation and migration that induced by M2-macrophages. miR-1587 targets IRF-7 to regulate its expression. Knockdown of IRF-7 reversed the effects of miR-1587 knockdown on cell proliferation and migration.Conclusion: Collectively, this study revealed that miR-1587/IRF-7 mediated the mechanism of M2-macrophages-induced breast cancer progression, and this would shed light on the further clinical therapy of breast cancer.

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Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion

Cited by 72 publications

References 45 publications

Tumor Milieu Controlled by RB Tumor Suppressor

Tumor Milieu Controlled by RB Tumor Suppressor

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

M2 macrophages contribute to cell proliferation and migration of breast cancer

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