HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses.
HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses.
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DOI：
10.18632/oncotarget.3641
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发表时间：
2015-07-10
期刊：
影响因子：
--
通讯作者：
Waltz SE
中科院分区：
文献类型：
--
作者：
Benight NM;Wagh PK;Zinser GM;Peace BE;Stuart WD;Vasiliauskas J;Pathrose P;Starnes SL;Waltz SE
罗恩受体在人乳腺癌中过表达，并与高转移和低生存率相关。小鼠乳腺上皮中罗恩过表达足以诱导具有高度转移的侵袭性乳腺肿瘤。尽管罗恩在乳腺癌中的作用已被充分证明，但很少有研究探讨内源性罗恩配体肝细胞生长因子样蛋白（HGFL）在乳腺肿瘤发生中的必要性。在此，在有或没有HGFL的乳腺上皮中过表达罗恩的小鼠中检查乳腺肿瘤生长和转移。HGFL消融降低了致癌罗恩激活，并延迟了乳腺肿瘤的发生。HGFL对肿瘤细胞的增殖和存活具有重要作用。HGFL损失导致肿瘤内巨噬细胞和T细胞数量增加。在HGFL缺陷小鼠中T细胞增殖和细胞毒性显著增加。HGFL活性肿瘤的生化分析显示局部HGFL产生增加，HGFL缺失降低β-catenin表达和NF-κB活化。在HGFL缺陷的肿瘤细胞中重新表达HGFL刺激细胞迁移和侵袭，协同激活NF-κB并减少凋亡。总之，这些结果证明了HGFL在促进乳腺肿瘤发生中的关键体内功能，并表明靶向HGFL可能抑制肿瘤生长并重新激活抗肿瘤免疫应答。
The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the necessity of the endogenous Ron ligand, hepatocyte growth factor-like protein (HGFL) in mammary tumorigenesis. Herein, mammary tumor growth and metastasis were examined in mice overexpressing Ron in the mammary epithelium with or without HGFL. HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation. HGFL was important for tumor cell proliferation and survival. HGFL loss resulted in increased numbers of macrophages and T-cells within the tumor. T-cell proliferation and cytotoxicity dramatically increased in HGFL deficient mice. Biochemical analysis of HGFL proficient tumors showed increased local HGFL production, with HGFL loss decreasing β-catenin expression and NF-κB activation. Re-expression of HGFL in HGFL deficient tumor cells stimulated cell migration and invasion with coordinate activation of NF-κB and reduced apoptosis. Together, these results demonstrate critical in vivo functions for HGFL in promoting breast tumorigenesis and suggest that targeting HGFL may inhibit tumor growth and reactivate anti-tumor immune responses.
影响因子：
4.6
作者：
Meyer, Sara E.;Waltz, Susan E.;Goss, Kathleen H.
通讯作者：
Goss, Kathleen H.