Yu Nanmeng, Puckett Shelby, Antinozzi Peter A, Cramer Scott D, Lyles Douglas S
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
J Virol. 2015 May;89(10):5250-63. doi: 10.1128/JVI.00257-15. Epub 2015 Mar 4.
A major challenge to oncolytic virus therapy is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. Variability in response may arise due to differences in the initial genetic lesions leading to cancer development. Alternatively, susceptibility to viral oncolysis may change during cancer progression. These hypotheses were tested using cells from a transgenic mouse model of prostate cancer infected with vesicular stomatitis virus (VSV). Primary cultures from murine cancers derived from prostate-specific Pten deletion contained a mixture of cells that were susceptible and resistant to VSV. Castration-resistant cancers contained a higher percentage of susceptible cells than cancers from noncastrated mice. These results indicate both susceptible and resistant cells can evolve within the same tumor. The role of Pten deletion was further investigated using clonal populations of murine prostate epithelial (MPE) progenitor cells and tumor-derived Pten(-/-) cells. Deletion of Pten in MPE progenitor cells using a lentivirus vector resulted in cells that responded poorly to interferon and were susceptible to VSV infection. In contrast, tumor-derived Pten(-/-) cells expressed higher levels of the antiviral transcription factor STAT1, activated STAT1 in response to VSV, and were resistant to VSV infection. These results suggest that early in tumor development following Pten deletion, cells are primarily sensitive to VSV, but subsequent evolution in tumors leads to development of cells that are resistant to VSV infection. Further evolution in castration-resistant tumors leads to tumors in which cells are primarily sensitive to VSV.
There has been a great deal of progress in the development of replication-competent viruses that kill cancer cells (oncolytic viruses). However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. The experiments presented here were to determine whether both sensitive and resistant cells are present in prostate cancers originating from a single genetic lesion in transgenic mice, prostate-specific deletion of the gene for the tumor suppressor Pten. The results indicate that murine prostate cancers are composed of both cells that are sensitive and cells that are resistant to oncolytic vesicular stomatitis virus (VSV). Furthermore, androgen deprivation led to castration-resistant prostate cancers that were composed primarily of cells that were sensitive to VSV. These results are encouraging for the use of VSV for the treatment of prostate cancers that are resistant to androgen deprivation therapy.
溶瘤病毒疗法面临的一个重大挑战是，即使这些癌症源自相同的组织类型，个体癌症对溶瘤病毒的敏感性也存在差异。反应的变异性可能是由于导致癌症发生的初始基因损伤不同所致。或者，在癌症进展过程中，对病毒溶瘤的易感性可能会发生变化。使用感染水疱性口炎病毒（VSV）的前列腺癌转基因小鼠模型的细胞对这些假设进行了测试。源自前列腺特异性Pten缺失的小鼠癌症的原代培养物中含有对VSV敏感和耐药的细胞混合物。去势抵抗性癌症中敏感细胞的百分比高于未去势小鼠的癌症。这些结果表明，敏感细胞和耐药细胞都可以在同一肿瘤内进化。使用小鼠前列腺上皮（MPE）祖细胞和肿瘤来源的Pten（-/-）细胞的克隆群体进一步研究了Pten缺失的作用。使用慢病毒载体在MPE祖细胞中缺失Pten导致细胞对干扰素反应不佳且对VSV感染敏感。相比之下，肿瘤来源的Pten（-/-）细胞表达更高水平的抗病毒转录因子STAT1，对VSV作出反应时激活STAT1，并对VSV感染具有抗性。这些结果表明，在Pten缺失后的肿瘤发生早期，细胞主要对VSV敏感，但肿瘤随后的进化导致了对VSV感染具有抗性的细胞的发展。去势抵抗性肿瘤的进一步进化导致肿瘤中的细胞主要对VSV敏感。
在能够杀死癌细胞的复制型病毒（溶瘤病毒）的开发方面已经取得了很大进展。然而，一个主要问题是，即使这些癌症源自相同的组织类型，个体癌症对溶瘤病毒的敏感性也存在差异。这里展示的实验旨在确定源自转基因小鼠单一基因损伤（肿瘤抑制基因Pten的前列腺特异性缺失）的前列腺癌中是否同时存在敏感细胞和耐药细胞。结果表明，小鼠前列腺癌由对溶瘤性水疱性口炎病毒（VSV）敏感的细胞和耐药细胞组成。此外，雄激素剥夺导致去势抵抗性前列腺癌，其主要由对VSV敏感的细胞组成。这些结果对于使用VSV治疗对雄激素剥夺疗法耐药的前列腺癌是令人鼓舞的。
