An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells.
An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells.
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DOI：
10.18632/oncotarget.15276
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发表时间：
2017-04-11
期刊：
影响因子：
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通讯作者：
Gotoh N
中科院分区：
文献类型：
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作者：
Sasahara A;Tominaga K;Nishimura T;Yano M;Kiyokawa E;Noguchi M;Noguchi M;Kanauchi H;Ogawa T;Minato H;Tada K;Seto Y;Tojo A;Gotoh N
癌症干细胞被认为是肿瘤生长、复发和抵抗常规癌症治疗的原因。然而，目前尚不清楚它们是如何在肿瘤组织中维持的。在这里，我们发现生长分化因子15 (GDF15)， TGFβ家族的一员，可能通过诱导其自身以自分泌/旁分泌方式表达来维持乳腺癌组织中的癌症干细胞样细胞。我们发现GDF15，而不是TGFβ，增加了几种乳腺癌细胞系和患者来源的原发性乳腺癌细胞的肿瘤球形成。正如预期的那样，tgf - β强烈刺激Smad2的磷酸化。GDF15也能刺激Smad2的磷酸化，但TGFβ信号抑制剂SB431542对GDF15诱导的肿瘤球形成效率没有显著影响。虽然TGFβ短暂激活ERK1/2，但GDF15诱导ERK1/2延长激活。MEK-ERK1/2信号的抑制剂U0126可以显著抑制gdf15诱导的肿瘤球的形成。此外，细胞因子阵列实验显示，GDF15能够诱导自身表达，而TGFβ不能；此外，它似乎形成一个自分泌/旁分泌回路来连续产生GDF15。此外，我们使用免疫组织化学方法发现GDF15在癌细胞和人乳腺癌组织中的表达水平存在异质性。这可能反映了癌症细胞群的异质性，包括癌症干细胞样细胞和其他癌细胞。我们的研究结果表明，GDF15通过GDF15- erk1 /2-GDF15回路诱导肿瘤球的形成，从而维持GDF15高表达的癌干细胞样细胞。靶向GDF15来打破这些回路应该有助于根除肿瘤。
Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFβ strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFβ signaling. Although TGFβ transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFβ, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.