Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone.
Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone.
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DOI：
10.1186/bcr1398
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Anderson RL
中科院分区：
文献类型：
--
作者：
Sloan EK;Pouliot N;Stanley KL;Chia J;Moseley JM;Hards DK;Anderson RL
异种移植模型和转移实验模型的研究表明，几种表达 β3 整合素的细胞群（包括内皮细胞、血小板和破骨细胞）与乳腺肿瘤进展有关。然而，由于乳腺癌原位人类异种移植模型向骨的转移性较差，并且实验模型绕过了原发肿瘤的形成，因此肿瘤特异性αvβ3对乳腺肿瘤从乳腺到骨的自发转移的精确贡献仍不清楚。我们使用自发性乳腺癌转移的同基因原位模型来测试转移至肺但不转移至骨的乳腺癌系（66cl4）中αvβ3的外源表达是否足以促进其从乳腺自发转移至骨。通过实时定量 PCR 分析将表达 αvβ3 的 66cl4 (66cl4beta3) 肿瘤细胞或对照 66cl4pBabe 接种到乳腺中后脊柱和肺部的肿瘤负荷。这些细胞在骨中生长和形成溶骨性病变的能力通过胫骨内注射肿瘤细胞后骨切片的组织学和抗酒石酸盐酸性磷酸酶染色来确定。在标准体外测定中评估了 66cl4pBabe 和 66cl4beta3 细胞的粘附、迁移和侵袭特性。与 66cl4pBabe 相比，66cl4beta3 肿瘤的脊柱转移负担增加了 20 倍。肺转移也观察到类似的趋势。 αvβ3 不会增加体外或体内乳腺中 66cl4 细胞的增殖。类似地，骨中 66cl4 细胞的增殖不需要 αvβ3，因为当直接注射到胫骨中时，66cl4pBabe 和 66cl4beta3 增殖的程度相同。然而，与 66cl4 肿瘤相比，66cl4beta3 肿瘤在胫骨中的生长增加了破骨细胞的募集和骨吸收。此外，αvβ3增加了66cl4肿瘤细胞粘附和αvβ3依赖性向骨基质蛋白的趋化迁移，以及它们在体外对骨源性可溶性因子的趋化反应。这些结果首次证明肿瘤特异性αvβ3有助于乳腺肿瘤自发转移至骨，并表明该受体在介导向骨因子的趋化和趋触迁移中发挥关键作用。
Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell adhesion and αvβ3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. These results demonstrate for the first time that tumor-specific αvβ3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors.
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影响因子：
4.8
作者：
Doerr, ME;Jones, JI
通讯作者：
Jones, JI
影响因子：
6.4
作者：
Deryugina, EI;Ratnikov, BI;Strongin, AY
通讯作者：
Strongin, AY
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
15.9
作者：
BROOKS, PC;STROMBLAD, S;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
6.2
作者：
Käkönen, SM;Mundy, GR
通讯作者：
Mundy, GR