Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Oncogene. 2010 Jul 8;29(27):3990-6. doi: 10.1038/onc.2010.137. Epub 2010 May 17.
Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted p53, ATM and Rb tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.
复制型溶瘤病毒在许多癌症的临床治疗中有很大的应用潜力。重要的是，许多溶瘤病毒候选物，如呼肠孤病毒和兔粘液瘤病毒，优先感染携带异常细胞信号通路的癌细胞。呼肠孤病毒和兔粘液瘤病毒对激活的 Ras 和 Akt 信号通路分别高度敏感，是它们对病毒溶瘤作用的特异性。然而，考虑到癌细胞群体的复杂性，其他肿瘤特异性信号通路也可能有助于病毒区分正常细胞和癌细胞。由于癌变是一个多步骤的过程，涉及癌基因的激活和肿瘤抑制基因的失活，我们推测不仅癌基因，而且肿瘤抑制基因可能在决定这些病毒对癌细胞的亲嗜性方面发挥重要作用。先前已经表明，许多细胞肿瘤抑制基因，如 p53、ATM 和 Rb，对于维持基因组稳定性很重要；这些肿瘤抑制因子的功能障碍可能会由于基因组不稳定性的积累或由于干扰凋亡信号而破坏完整的细胞抗病毒活性。因此，我们推测，具有功能失调的肿瘤抑制因子的细胞可能对这些溶瘤病毒的挑战表现出增强的易感性，就像以前腺病毒所看到的那样。我们在这里报告，呼肠孤病毒和兔粘液瘤病毒优先感染携带功能失调或缺失的 p53、ATM 和 Rb 肿瘤抑制基因的癌细胞，而不是保留这些基因正常拷贝的细胞。因此，这些病毒的溶瘤作用可能受到致癌激活和肿瘤抑制状态的影响。
