Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma

Lamanuzzi, Aurelia; Saltarella, Ilaria; Desantis, Vanessa; Frassanito, Maria Antonia; Leone, Patrizia; Racanelli, Vito; Nico, Beatrice; Ribatti, Doménico; Ditonno, Paolo; Prete, Marcella; Solimando, Antonio Giovanni; Dammacco, F; Vacca, Angelo; Ria, Roberto

doi:10.18632/oncotarget.25003

Cited by 53 publications

(51 citation statements)

References 55 publications

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“…It has been shown that selective or targeted mTORC2 inhibition causes reduced cell proliferation, tumor size, and angiogenesis in several types of cancers including colon cancer, breast cancer and multiple myeloma [49][50][51][52][53]. Differential effects of dose-interval schedules of rapamycin (or rapalogs) on colon cancer have also been investigated.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Dorvash

Farahmandnia

Mosaddeghi

et al. 2019

Preprint

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Signal integration in the mTOR pathway plays a vital role in cell fate decision making in cancer cells.As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein. 2-Components like Phosphatidic Acid further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier's principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. The model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.

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Section: Discussionmentioning

confidence: 99%

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Dorvash

Farahmandnia

Mosaddeghi

et al. 2019

Preprint

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“…Signals for angiogenesis include angiopoietin, interleukin (IL) 8, FGF, VEGF, and PDGF. PI3K-AKT signaling pathway regulates angiogenesis induction and stabilization of the vessel [119], with potential multifaced therapeutic windows in a broad spectrum of malignancies [186,187]. In addition, HIF1 stimulates the synthesis and secretion of VEGF in cancer cells.…”

Section: Angiogenesismentioning

confidence: 99%

Oncogenic Signaling Pathways in Cancer: An Overview

Derakhshani¹,

Rostami²,

Taefehshokr³

et al. 2020

Preprint

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Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

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“…The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival, and actin rearrangement. mTOR is made of two independent complexes, mTORC1, involved in protein synthesis and autophagy inhibition, and mTORC2, involved in progression promotion, survival, actin reorganization, and drug resistance [125][126][127]. In MM endothelial, a significantly higher activation of mTORC2 have been demonstrated.…”

Section: Soluble Factors and Transduction Pathwaysmentioning

confidence: 99%

“…In MM endothelial, a significantly higher activation of mTORC2 have been demonstrated. Its inhibition induces a reduction of the angiogenic abilities of MM endothelial cells, suggesting a major role of mTORC2 in the "angiogenic switch" and indicates that mTORC2 might be a new antiangiogenic target in MM [127].…”

Section: Soluble Factors and Transduction Pathwaysmentioning

confidence: 99%

Angiogenesis and Antiangiogenesis in Multiple Myeloma

Ria¹,

Solimando²,

Melaccio³

et al. 2019

Update on Multiple Myeloma

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Multiple myeloma progression is characterized by a dense interaction between cancer cells and bone marrow microenvironment. The interactions of myeloma cells with various stromal cells and extracellular matrix components are the main regulator of the biological processes that underlie the progression of the disease and of the classic symptomatology correlated. The bone marrow of myeloma patients has recognized autocrine and paracrine loops that regulate multiple signaling pathways and the malignant phenotype of plasma cells. One of the pivotal biological processes which are responsible for myeloma progression is the formation of new vessels from existing ones, known as angiogenesis. It represents a constant hallmark of disease progression and a characteristic feature of the active phase of the disease. Near angiogenesis, other two ancestral processes were active in the bone marrow: vasculogenesis and vasculogenic mimicry. These processes are mediated by the angiogenic cytokines, interleukins, and inflammatory cytokines directly secreted by plasma cells and stromal cells. Neovascularization is also mediated by direct interaction between plasma cells and the various components of bone marrow microenvironment. The observation of the increased bone marrow angiogenesis in multiple myeloma and its correlation with disease activity and overall survival led to consider angiogenesis as a new target in the treatment of multiple myeloma.

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Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma

Cited by 53 publications

References 55 publications

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Oncogenic Signaling Pathways in Cancer: An Overview

Angiogenesis and Antiangiogenesis in Multiple Myeloma

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