Clinical and Prognostic Implications of Roundabout 4 (Robo4) in Adult Patients with Acute Myeloid Leukemia

Chen, Yin Kai; Hou, Hsin An; Tang, Jih-Luh; Jhuang, Jie Yang; Lai, Yan Jun; Lee, Ming Cheng; Kuo, Yueh‐Hsiung; Chou, Wen‐Chien; Liu, Chieh‐Yu; Lin, Chung-Wu; Chuang, Shih Sung; Chen, Chien Yuan; Tseng, Mei‐Hui; Huang, Chi Fei; Chiang, Yu‐Chih; Lee, Fen Yu; Liu, Ming Chih; Liu, Chia Wen; Yao, Ming; Huang, Shang Yi; Ko, Bor-Sheng; Hsu, Shih Ping; Wu, Shipher; Tsay, Woei; Chen, Yao Chang; Tien, Hwei‐Fang

doi:10.1371/journal.pone.0119831

Cited by 8 publications

(13 citation statements)

References 45 publications

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“…demonstrated, that Robo 4 was significantly upregulated in glioma tissues compared with normal brain tissue 28. Further total Robo 4 expression was significantly higher in bone marrow specimens of acute myeloid leukemia patients compared to normal bone marrow donors 30. These findings are in line with our observations in PCa tissue, where Robo 4 is higher expressed in cancerous tissue compared to normal prostate tissue, respectively.…”

Section: Discussionsupporting

confidence: 89%

Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature

et al. 2019

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Background: The magic roundabout receptor 4 (Robo 4) is a tumor endothelial marker expressed in the vascular network of various tumor entities. However, the role of Robo 4 in prostate cancer (PCa), the second common cause of cancer death among men in -developed countries, has not been described yet. Thus, the present study investigates for the first time the impact of Robo 4 in PCa both in the clinical setting and in vitro.Methods and Results: Immunohistochemical analyses of benign and malignant prostate tissue samples of 95 PCa patients, who underwent radical prostatectomy (RPE), revealed a significant elevated expression of Robo 4 as well as its ligand Slit 2 protein in cancerous tissue compared to benign. Moreover, increased Robo 4 expression was associated with higher Gleason score and pT stage. In advanced stage we observed a hypothesis-generating trend that high Robo 4 and Slit 2 expression is associated with delayed development of tumor recurrence compared to patients with low Robo 4 and Slit 2 expression, respectively.In contrast to so far described exclusive expression of Robo 4 in the tumor vascular network, our analyses showed that in PCa Robo 4 is not only expressed in the tumor stroma but also in cancer epithelial cells. This finding was also confirmed in vitro as PC3 PCa cells express Robo 4 on mRNA as well as protein level. Overexpression of Robo 4 in PC3 as well as in Robo 4 negative DU145 and LNCaP PCa cells was associated with a significant decrease in cell-proliferation and cell-viability.Conclusion: In summary we observed that Robo 4 plays a considerable role in PCa development as it is expressed in cancer epithelial cells as well as in the surrounding tumor stroma. Moreover, higher histological tumor grade was associated with increased Robo 4 expression; controversially patients with high Robo 4 tend to exert lower biochemical recurrence possibly reflecting a protective role of Robo 4.

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Section: Discussionsupporting

confidence: 89%

Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature

et al. 2019

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“…56 In addition, ROBO4 has recently been identified in murine HSCs 57,58 and human AML cells. 59 We found that HSCs and LSCs express ROBO4. Although CML LSCs expressed ROBO4 at high levels, AML LSCs expressed only low amounts of ROBO4.…”

Section: Discussionmentioning

confidence: 79%

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

Herrmann

Sadovnik²,

Eisenwort³

et al. 2020

Blood Advances

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In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n = 274) or CML (n = 97) and controls (n = 288) for expression of cell membrane antigens on CD34+/CD38− and CD34+/CD38+ cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD34+/CD38− and CD34+/CD38+ cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD34+/CD38− LSCs exhibited an almost invariable aberration profile, defined as CD25+/CD26+/CD56+/CD93+/IL-1RAP+. By contrast, in patients with AML, CD34+/CD38− cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD34+/CD38− LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

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“…Robo4 expression was initially detected in the vasculature at sites of active angiogenesis, including the placenta and various tumors [5]. Many subsequent studies have investigated Robo4 expression in physiological and pathological angiogenesis and revealed that Robo4 is involved in regulating angiogenesis during vascular development [31,49,108] in tumors [11,[109][110][111] and during ocular neovascularization [10,25,50,112,113].…”

Section: The Function Of Robo4 In Angiogenesismentioning

confidence: 99%

“…In addition to serving as an antiangiogenic target in carcinoma, Robo4 also functions as a biomarker for clinical characteristics and prognosis. Patients with acute myeloid leukemia (AML) presenting high Robo4 expression have a significantly shorter disease-free survival (DFS) and overall survival (OS) than patients with lower Robo4 expression [111]. However, increased Robo4 expression correlates with an increased OS of patients with non-small-cell lung cancer [131].…”

Section: Robo4 and Tumorsmentioning

confidence: 99%

Regulatory mechanisms of Robo4 and their effects on angiogenesis

et al. 2019

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Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis.

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Clinical and Prognostic Implications of Roundabout 4 (Robo4) in Adult Patients with Acute Myeloid Leukemia

Cited by 8 publications

References 45 publications

Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature

Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

Regulatory mechanisms of Robo4 and their effects on angiogenesis

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