Vascular mimicry: changing the therapeutic paradigms in cancer

Maroufi, Nazila Fathi; Taefehshokr, Sina; Rashidi, Mohammad‐Reza; Taefehshokr, Nima; Khoshakhlagh, Mahdieh; Isazadeh, Alireza; Mokarizadeh, Narmin; Nouri, Mohammad

doi:10.1007/s11033-020-05515-2

Cited by 56 publications

(18 citation statements)

References 171 publications

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“…Consequently, the microchannels allow for increased passive oxygen and nutrient diffusion. Tumor cells may also follow along the blood vessels, whereby the blood vessel structures act as guides, allowing tumor cells to spread both internally into and externally around existing blood vessels ( Ge and Luo, 2018 ; Zavyalova et al, 2019 ; Fathi Maroufi et al, 2020 ; Mei et al, 2020 ; Wechman et al, 2020 ; Zhang et al, 2020 ; Majidpoor and Mortezaee, 2021 ; Ribatti and Pezzella, 2021 ; Treps et al, 2021 ; Wei et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Cocola

Magnaghi

Abeni

et al. 2021

Front. Cell. Neurosci.

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Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Cocola

Magnaghi

Abeni

et al. 2021

Front. Cell. Neurosci.

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“…A growing body of evidence has demonstrated that the interaction between the tumor microenvironment (TME) and tumor cells plays a critical role in cancer development and progression (8,9). Tumor VM formation with its non-cancer cells as macrophages and fibroblasts is associated with cancer cells invasiveness and metastasis (10,11) and the interaction of the TME in VM development is not yet understood. Therefore, elucidating mechanisms through which this interaction promotes VM formation is pivotal because they can provide new therapeutic opportunities.…”

Section: Introductionmentioning

confidence: 99%

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

Tsai

Liu

et al. 2021

Front. Oncol.

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BackgroundAngiogenesis is required for tumor development and metastasis, which is a major part in a pro-tumor microenvironment. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression.ObjectivesTo validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer.MethodsIn this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways.ResultsH1299 and CL1-0 lung cancer cells were unable to form capillary-like structures. VM formation was induced by cancer-associated fibroblast (CAFs) in both in vitro and in vivo experiments. Notch2–Jagged1 cell–cell contact between cancer cells and CAFs contributes to the formation of VM networks, supported by Notch intracellular domain (NICD) 2 nuclear translocation and N2ICD target gene upregulated in lung cancer cells mixed with CAFs. The polarization of tumor-promoting N2-type neutrophil was increased by VM networks consisting of CAF and cancer cells. The intravasation of cancer cells and N2-type neutrophils were increased because of the loose junctions of VM. Disruption of cancer cell–CAF connections by a γ‐secretase inhibitor enforced the anticancer effect of anti‐vascular endothelial growth factor antibodies in a mouse model.ConclusionThis study provides the first evidence that CAFs induce lung cancer to create vascular-like networks. These findings suggest a therapeutic opportunity for improving antiangiogenesis therapy in lung cancer.

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“…Since anti-angiogenic agents were shown to effectively slow the growth and metastasis of human melanoma, it is not surprising that the efficacy of these agents in augmenting the benefits of other promising therapies is being tested in clinical trials ( 87 , 96 ). Unfortunately, anti-angiogenic monotherapies in melanoma did not show remarkable clinical responses and it has been suggested that vascular mimicry plays an important role in improving blood supply to the tumor to support its growth and dissemination ( 97 , 98 ). It is possible that delivering therapeutics that block angiogenesis or vascular mimicry to early-stage melanoma patients, may impede metastasis in two ways: 1) block nutrient and oxygen flow to the primary tumor and 2) hamper primary tumor cells’ dissemination by inhibiting entry into circulation.…”

Section: Mechanisms and Routes For Melanoma Metastasismentioning

confidence: 99%

Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities

2021

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Melanoma, a cancer of the skin, arises from transformed melanocytes. Melanoma has the highest mutational burden of any cancer partially attributed to UV induced DNA damage. Localized melanoma is “curable” by surgical resection and is followed by radiation therapy to eliminate any remaining cancer cells. Targeted therapies against components of the MAPK signaling cascade and immunotherapies which block immune checkpoints have shown remarkable clinical responses, however with the onset of resistance in most patients, and, disease relapse, these patients eventually become refractory to treatments. Although great advances have been made in our understanding of the metastatic process in cancers including melanoma, therapy failure suggests that much remains to be learned and understood about the multi-step process of tumor metastasis. In this review we provide an overview of melanocytic transformation into malignant melanoma and key molecular events that occur during this evolution. A better understanding of the complex processes entailing cancer cell dissemination will improve the mechanistic driven design of therapies that target specific steps involved in cancer metastasis to improve clinical response rates and overall survival in all cancer patients.

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Vascular mimicry: changing the therapeutic paradigms in cancer

Cited by 56 publications

References 171 publications

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer

Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities

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