Vascular Normalization: A New Window Opened for Cancer Therapies

Yang, Ting; Xiao, Hongqi; Liu, Xiaoxia; Wang, Zhihui; Zhang, Qingbai; Wei, Nianjin; Guo, Xinggang

doi:10.3389/fonc.2021.719836

Cited by 43 publications

(39 citation statements)

References 295 publications

(385 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, PELP1 suppression combined with chemotherapeuticdrug has a synergistic anti-tumor effect. It has been reported that targeting PELP1 can induce tumor vessels normalization through attenuating angiogenesis and enhance the efficacy of chemotherapy via increasing the delivery of chemotherapeutic drug into tumor tissue ( Figure 7 ).Currently, the main problem of tumor vascular normalization is that the window period is short, and the window period is difficult to predict [ 50 ]. These issues were not further explored in this study.…”

Section: Discussionmentioning

confidence: 99%

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

Zhu

Wang

et al. 2022

Cancers

View full text Add to dashboard Cite

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

Zhu

Wang

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Normal vasculature is needed for immunosurveillance and efficient detection and killing of cancer cells by immune cells. Disorganized tumor vessels create a selective immune cell barrier limiting the extravasation of immune cells, particularly the cytotoxic T lymphocytes into blood vessels and tumor tissue (Yang et al, 2021). Further, hypoxia in the tumor microenvironment promotes lactate accumulation, extracellular acidosis, VEGF overexpression, and VEGFR activation, all of which are known drivers of immune cell tolerance and immunosuppressive status (Mendler et al, 2012;Vaupel and Multhoff, 2017).…”

Section: Immunotherapeutic Drugsmentioning

confidence: 99%

“…The immune response and vascular normalization seem to be mutually regulated (Fukumura et al, 2018;Huang et al, 2018). Normalization of the tumor vasculature improves the infiltration of immune effector cells into tumors enhancing antitumor immune activity (Fukumura et al, 2018;Solimando et al, 2020;Yang et al, 2021). Likewise, immunotherapy can promote vascular normalization which further improves the effectiveness of immunotherapeutic drugs and response to anti-angiogenic therapies (Huang et al, 2018;Ciciola et al, 2020;Yang et al, 2021).…”

Section: Immunotherapeutic Drugsmentioning

confidence: 99%

“…Normalization of the tumor vasculature improves the infiltration of immune effector cells into tumors enhancing antitumor immune activity (Fukumura et al, 2018;Solimando et al, 2020;Yang et al, 2021). Likewise, immunotherapy can promote vascular normalization which further improves the effectiveness of immunotherapeutic drugs and response to anti-angiogenic therapies (Huang et al, 2018;Ciciola et al, 2020;Yang et al, 2021). In preclinical models of breast cancer, immune checkpoint inhibitors induced normalization of tumor vasculature and increased infiltration of immune cells into breast tumors (Tian et al, 2017;Zheng et al, 2020).…”

Section: Immunotherapeutic Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches

et al. 2022

View full text Add to dashboard Cite

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

show abstract

“…However, tumor cells not only adapt and survive under these stressful conditions, but also use this abnormal vascular network to create a shield that protects them from the immune system and therapeutic agents. The conversion of this immature endothelium into a more “normal” vascular network is, therefore, a promising therapeutic strategy for enhancing drug delivery and boosting immunotherapy [ 1 , 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Carmona-Rodríguez

Martínez-Rey

Martín-González

et al. 2022

Cancers

View full text Add to dashboard Cite

The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors.

show abstract

Vascular Normalization: A New Window Opened for Cancer Therapies

Cited by 43 publications

References 295 publications

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Contact Info

Product

Resources

About