ACVR2B antagonism as a countermeasure to multi-organ perturbations in metastatic colorectal cancer cachexia.
ACVR2B antagonism as a countermeasure to multi-organ perturbations in metastatic colorectal cancer cachexia.
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DOI：
10.1002/jcsm.12642
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Bonetto A
中科院分区：
文献类型：
--
作者：
Huot JR;Pin F;Narasimhan A;Novinger LJ;Keith AS;Zimmers TA;Willis MS;Bonetto A
晚期结直肠癌（CRC）通常伴有肝转移以及恶病质的发展，恶病质是一种主要影响骨骼（SKM）和心肌的多器官共病。已知激活素受体2B型（ACVR 2B）信号传导导致SKM消耗，并且其抑制恢复癌症中的SKM质量和肿瘤存活。使用最近生成的小鼠模型，在此我们测试了ACVR 2B阻断是否可以在转移性CRC存在的情况下保护多个器官，包括骨骼肌和心肌。NSG雄性小鼠（8周龄）脾内注射HCT 116人CRC细胞（mHCT 116），而假手术动物接受生理盐水（每组n = 5-10）。假手术和荷瘤小鼠每周接受ACVR 2B/Fc（一种ACVR 2B的合成肽抑制剂）注射。mHCT 116宿主显示脂肪量（− 79%，P < 0.0001）、骨量（− 39%，P < 0.05）和SKM质量（四头肌：− 22%，P < 0.001）减少，与肌肉横截面积（− 24%，P < 0.01）和跖屈力（− 28%，P < 0.05）减少一致。此外，尽管mHCT 116宿主的心脏大小仅受到中度影响，但心脏功能显著受损（射血分数%：-16%，P < 0.0001;缩短分数%：-25%，P < 0.0001）。相反，ACVR 2B/Fc在肿瘤宿主中保留了脂肪质量（+238%，P < 0.001）、骨量（+124%，P < 0.0001）、SKM质量（四头肌：+31%，P < 0.0001）、大小（横截面积：+43%，P < 0.0001）和跖屈力（+28%，P < 0.05）。在接受ACVR 2B/Fc的肿瘤宿主中，心脏功能也完全保留（射血分数%：+19%，P < 0.0001），尽管对心脏大小没有影响。心肌的RNA测序分析显示，在用ACVR 2B/Fc治疗的肿瘤宿主中，与心脏发育和收缩相关的基因得到拯救。我们的转移性CRC模型通过在mHCT 116宿主中显示脂肪、骨和SKM沿着肌肉力量降低来重现恶病质的多系统紊乱。此外，有严重心功能不全的证据，我们的数据支持心脏恶病质在转移性结直肠癌发生中的发展。值得注意的是，ACVR 2B拮抗作用保留了脂肪组织、骨和SKM，而肌肉和心脏功能在治疗后完全维持。总之，我们的观察结果表明ACVR 2B信号传导参与了转移性CRC中多器官扰动的发展，并进一步表明ACVR 2B代表了一种有希望的治疗靶点，可在癌症恶病质中保护身体组成和功能。
Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi‐organ co‐morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham‐operated animals received saline (n = 5–10 per group). Sham and tumour‐bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. mHCT116 hosts displayed losses in fat mass ( − 79%, P < 0.0001), bone mass ( − 39%, P < 0.05), and SKM mass (quadriceps: − 22%, P < 0.001), in line with reduced muscle cross‐sectional area ( − 24%, P < 0.01) and plantarflexion force ( − 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: − 16%, P < 0.0001; fractional shortening %: − 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass ( + 238%, P < 0.001), bone mass ( + 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross‐sectional area: + 43%, P < 0.0001) and plantarflexion force ( + 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Our metastatic CRC model recapitulates the multi‐systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi‐organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.
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影响因子：
5.2
作者：
Ballaro, Riccardo;Penna, Fabio;Costelli, Paola
通讯作者：
Costelli, Paola
DOI：
10.1152/ajpheart.00302.2019
发表时间：
2020-02-01
影响因子：
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影响因子：
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通讯作者：
Huang, Congxin
DOI：
10.1152/ajpendo.00001.2019
发表时间：
2019-06-01
影响因子：
5.1
作者：
Czaja, Wioletta;Nakamura, Yukiko K.;Rodgers, Buel D.
通讯作者：
Rodgers, Buel D.
影响因子：
2.5
作者：
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