Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance

Cao, Zhongwei; Ding, Bi-Sen; Guo, Peipei; Lee, Sharrell B.; Butler, Jason M.; Casey, Stephanie C.; Simons, Michael; Tam, Wayne; Felsher, Dean W.; Shido, Koji; Rafii, Arash; Scandura, Joseph M.; Rafii, Shahin

doi:10.1016/j.ccr.2014.02.005

Cited by 201 publications

(191 citation statements)

References 58 publications

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“…The effect of EC-secreted factors on the regulation of tissue and tumor growth has recently been highlighted (35)(36)(37), emphasizing the potential benefit of targeting the cross talk between ECs and tumor cells to supplement conventional antiangiogenic therapies. However, we do not exclude that there may be additional cells in the tumor microenvironment that express low levels of Pdgfd.…”

Section: Discussionmentioning

confidence: 99%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, plateletderived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development.However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

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Section: Discussionmentioning

confidence: 99%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Of note, the inhibition of IGF1R, using both specific inhibitors and siRNA, resulted in a relevant reduction in T-ALL survival and proliferation. On the same line, Cao et al [73] have recently shown that angiomodulin effectively inhibits the IGFR-1 receptor on tumor cells and delays the growth of cancer cells, suggesting its putative usage in the treatment of hematological disorders and many other human neoplasms addicted to IGF-1 signaling. In the case of T-ALL, the aberrant activation of Notch signaling enhances the expression of IGF1R signaling, making them highly responsive to IGF-1 provided by microenvironment [74].…”

Section: Breaking the Alliancementioning

confidence: 97%

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

Giacomo¹,

Fiore²,

Kyriakides³

et al. 2017

Clin Diagn Pathol

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T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy associated with a high risk of treatment failure. Efforts to improve outcomes have focused on underlying genetic defects. However, strong evidence suggests that leukemic cells prime a maladapted niche that in turn provides signals capable of sustaining the dormancy of leukemia initiating cells and protects them from toxic chemotherapeutic agents. Here, we aim to describe how key components of the bone marrow microenvironment are essential for leukemia initiation and progression. Although many mechanisms have been recently discovered, further studies are required to fully dissect the molecular mechanisms governing the bidirectional interactions between tumor and host cells. We predict that these new discoveries will pave the way for the implementation of novel therapeutic strategies and will eventually lead to the eradication of the drug-resistant cells, substantially and ultimately enhancing cure rates for T-ALL patients.

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“…In other situations, Hey proteins promote mesenchymal-epithelial (37). Epithelium-derived Jagged1 activates Hey1 which then promotes metastatic lymphoma cell chemotherapy resistance as well as progression in the tumor perivascular niche (38).…”

Section: The Roles Of Hey Proteins In Cancer Metastasismentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance

Cited by 201 publications

References 58 publications

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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