Punctate LC3B expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome.
Punctate LC3B expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome.
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DOI：
10.1158/1078-0432.ccr-11-1282
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发表时间：
2012-01-15
期刊：
影响因子：
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通讯作者：
Pawelek JM
中科院分区：
文献类型：
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作者：
Lazova R;Camp RL;Klump V;Siddiqui SF;Amaravadi RK;Pawelek JM
癌症中自噬的测量及其与组织病理学分级或临床结果的相关性有限。因此，我们通过分析 20 种癌症的近 1400 个肿瘤，研究了 LC3B 作为自噬体标记物，重点关注与黑色素瘤和乳腺癌临床结果的相关性。使用抗体与 LC3 同种型 B (LC3B) 和 Ki-67 开发了用于自动定量分析 (AQUA) 的染色方案。采用了经过临床注释的乳腺癌和黑色素瘤 TMA 以及多肿瘤阵列。开发了 AQUA 程序来定量细胞的点状和扩散区室中 LC3B 的分布。大多数肿瘤的 LC3B 染色为中度至高度。在高 LC3B 强度下，点状 LC3B 占据的面积百分比提高了 3-5 倍。在乳腺癌和黑色素瘤 TMA 中，LC3B 和 Ki-67 显示出很强的相关性 (p < 0.0001)，在多肿瘤 TMA 中，有丝分裂图最常见于 LC3B 表达最高的肿瘤 (p < 0.002)。在乳腺癌中，与淋巴结阴性原代相比，LC3B 表达在淋巴结阳性原发中升高，并与核分级增加和生存期缩短相关。在没有生存数据的黑色素瘤 TMA 中，LC3B 水平在淋巴结、内脏和皮肤转移中最高。结果揭示了 LC3B 在恶性肿瘤中的常见表达，并支持新的证据表明自噬在癌症进展中发挥着重要作用。高 LC3B 与增殖、侵袭和转移、高核级别和较差的结果相关。因此，自噬是实体瘤治疗脆弱性的一个关键靶点。
Measurement of autophagy in cancer and correlation with histopathologic grading or clinical outcomes has been limited. Accordingly, we investigated LC3B as an autophagosome marker by analyzing nearly 1400 tumors from 20 types of cancer, focussing on correlations with clinical outcomes in melanoma and breast cancer. Staining protocols were developed for automated quantitative analysis (AQUA) using antibodies vs LC3 isoform B (LC3B) and Ki-67. Clinically annotated breast and melanoma TMA’s and a multitumor array were employed. An AQUA program was developed to quantitate LC3B distribution in punctate and diffuse compartments of the cell. LC3B staining was moderate to high in the large majority of tumors. The % area occupied by punctate LC3B was elevated 3–5 fold at high LC3B intensities. In breast cancer and melanoma TMAs, LC3B and Ki-67 showed strong correlations (p < 0.0001) and in multitumor TMAs mitotic figures were most often seen in tumors with highest LC3B expression (p < 0.002). In breast cancer, LC3B expression was elevated in node-positive vs node-negative primaries and associated with increased nuclear grade and shortened survival. In a melanoma TMA with no survival data, LC3B levels were highest in nodal, visceral and cutaneous metastases. The results reveal a common expression of LC3B in malignancy and support emerging evidence that autophagy plays a significant role in cancer progression. High LC3B was associated proliferation, invasion and metastasis, high nuclear grade and worse outcome. Thus autophagy presents a key target of therapeutic vulnerability in solid tumors.