M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.
M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.
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DOI：
10.1371/journal.pone.0021106
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kishimoto TK
中科院分区：
文献类型：
--
作者：
Zhou H;Roy S;Cochran E;Zouaoui R;Chu CL;Duffner J;Zhao G;Smith S;Galcheva-Gargova Z;Karlgren J;Dussault N;Kwan RY;Moy E;Barnes M;Long A;Honan C;Qi YW;Shriver Z;Ganguly T;Schultes B;Venkataraman G;Kishimoto TK
硫酸乙酰肝素蛋白聚糖（HSPG）通过呈递生长因子、细胞因子和其他可溶性因子在塑造肿瘤微环境中发挥关键作用，所述可溶性因子对于宿主细胞募集和活化以及促进肿瘤进展、转移和存活至关重要。M402是一种合理设计的非细胞毒性硫酸乙酰肝素（HS）模拟物，旨在抑制肿瘤-宿主细胞相互作用中涉及的多种因子，包括VEGF、FGF 2、SDF-1α、P-选择素和乙酰肝素酶。单次皮下剂量的M402有效地抑制了实验转移模型中B16 F10鼠黑素瘤细胞向肺的接种。荧光标记的M402在原发性肿瘤中表现出选择性蓄积。原发性肿瘤的免疫组织学分析显示，M402治疗的动物中微血管密度降低，表明抗血管生成是体内涉及的机制之一。M402治疗还使荷瘤小鼠中髓源性抑制细胞的循环水平正常化。在原位4 T1小鼠乳腺癌模型中，M402单独或与顺铂或多西他赛联合长期给药可抑制自发转移并延长生存期。这些数据表明，调节HSPG生物学代表了靶向参与肿瘤进展和转移的多种因素的新方法。
Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.
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影响因子：
8.8
作者：
Dredge, K.;Hammond, E.;Handley, P.;Gonda, T. J.;Smith, M. T.;Vincent, C.;Brandt, R.;Ferro, V.;Bytheway, I.
通讯作者：
Bytheway, I.
影响因子：
11.2
作者：
Ludwig, RJ;Boehme, B;Gille, J
通讯作者：
Gille, J
影响因子：
2.9
作者：
Hoogewerf, AJ;Kuschert, GSV;Wells, TNC
通讯作者：
Wells, TNC
影响因子：
--
作者：
Casu B;Vlodavsky I;Sanderson RD
通讯作者：
Sanderson RD
DOI：
10.1073/pnas.0808041105
发表时间：
2008-10-21
影响因子：
11.1
作者：
Leary, Rebecca J.;Lin, Jimmy C.;Velculescu, Victor E.
通讯作者：
Velculescu, Victor E.