PDF(Pubmed)
Abstract：
BACKGROUND: In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.
OBJECTIVE: Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways.
RESULTS: 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation.
CONCLUSIONS: Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.
OBJECTIVE: Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways.
RESULTS: 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation.
CONCLUSIONS: Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.
摘要：
背景：在肿瘤中，体细胞突变可能通过改变的调节途径驱动DNA损伤反应（DDR），增加基因组不稳定性和增殖活性。这些考虑导致了针对癌症的标准治疗策略：破坏肿瘤的突变激活的DNA修复途径。
目的：证明癌细胞不是被杀死的敌人，而是它们是具有生理调节途径残余的人类细胞。
结果：1.基因组不稳定和癌症发展可能源于雌激素信号的缺陷，而不是过度的雌激素信号；2.具有基因组不稳定性的健康细胞表现出体细胞突变，帮助DNA恢复；3.肿瘤细胞中的体细胞突变旨在恢复DNA损伤，而不是进一步的基因组紊乱；4.在肿瘤中，雌激素信号驱动DNA稳定的途径，导致凋亡性死亡;5.在肿瘤周围细胞浸润中，肿瘤的基因组损伤诱导炎性细胞因子分泌和雌激素合成增加。在炎症细胞中，增加的生长因子受体(GFR)信号赋予雌激素受体(ER)的无配体激活;6.在对基因毒性治疗有反应的乳腺癌细胞中，组成型突变有助于雌激素信号的上调和相应的细胞凋亡。在对基因毒性治疗无反应的乳腺肿瘤中，通过配体或非配体途径激活ER的可能性已经耗尽，导致进一步的基因组不稳定和无限制的增殖。
结论：在分子水平上了解人类肿瘤的真实特征和行为表明，我们应该学习肿瘤的基因组修复方法，并通过支持治疗来遵循这些方法，而不是引发额外的基因组损伤。
目的：证明癌细胞不是被杀死的敌人，而是它们是具有生理调节途径残余的人类细胞。
结果：1.基因组不稳定和癌症发展可能源于雌激素信号的缺陷，而不是过度的雌激素信号；2.具有基因组不稳定性的健康细胞表现出体细胞突变，帮助DNA恢复；3.肿瘤细胞中的体细胞突变旨在恢复DNA损伤，而不是进一步的基因组紊乱；4.在肿瘤中，雌激素信号驱动DNA稳定的途径，导致凋亡性死亡;5.在肿瘤周围细胞浸润中，肿瘤的基因组损伤诱导炎性细胞因子分泌和雌激素合成增加。在炎症细胞中，增加的生长因子受体(GFR)信号赋予雌激素受体(ER)的无配体激活;6.在对基因毒性治疗有反应的乳腺癌细胞中，组成型突变有助于雌激素信号的上调和相应的细胞凋亡。在对基因毒性治疗无反应的乳腺肿瘤中，通过配体或非配体途径激活ER的可能性已经耗尽，导致进一步的基因组不稳定和无限制的增殖。
结论：在分子水平上了解人类肿瘤的真实特征和行为表明，我们应该学习肿瘤的基因组修复方法，并通过支持治疗来遵循这些方法，而不是引发额外的基因组损伤。
