Bazak Jerzy, Korytowski Witold, Girotti Albert W
Department of Biophysics, Jagiellonian University, 30-387 Krakow, Poland.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cancers (Basel). 2019 Oct 28;11(11):1674. doi: 10.3390/cancers11111674.
Tumor cells exposed to stress-inducing radiotherapy or chemotherapy can send signals to non- or minimally exposed bystander cells. Bystander effects of ionizing radiation are well established, but little is known about such effects in non-ionizing photodynamic therapy (PDT). Our previous studies revealed that several cancer cell types upregulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after a moderate 5-aminolevulinic acid (ALA)-based PDT challenge. The NO signaled for cell resistance to photokilling as well as greater growth, migration and invasion of surviving cells. Based on this work, we hypothesized that diffusible NO produced by PDT-targeted cells in a tumor might elicit pro-growth/migration responses in non-targeted bystander cells. In the present study, we tested this using a novel approach, in which ALA-PDT-targeted human cancer cells on culture dishes (prostate PC3, breast MDA-MB-231, glioma U87, or melanoma BLM) were initially segregated from non-targeted bystanders via impermeable silicone-rimmed rings. Several hours after LED irradiation, rings were removed, and both cell populations analyzed for various post-hν responses. For a moderate and uniform level of targeted cell killing by PDT (~25%), bystander proliferation and migration were both enhanced. Enhancement correlated with iNOS/NO upregulation in surviving targeted cells in the following order: PC3 > MDA-MB-231 > U87 > BLM. If occurring in an actual tumor PDT setting and not suppressed (e.g., by iNOS activity or transcription inhibitors), then such effects could compromise treatment efficacy or even stimulate disease progression if PDT's anti-tumor potency is not great enough.
暴露于诱导应激的放疗或化疗的肿瘤细胞可向未暴露或仅轻微暴露的旁观者细胞发送信号。电离辐射的旁观者效应已得到充分证实，但对于非电离光动力疗法（PDT）中的此类效应知之甚少。我们之前的研究表明，几种癌细胞类型在基于适度的5-氨基乙酰丙酸（ALA）的PDT刺激后会上调诱导型一氧化氮合酶（iNOS）和一氧化氮（NO）。NO发出信号，使细胞对光杀伤产生抗性，并使存活细胞具有更强的生长、迁移和侵袭能力。基于这项工作，我们假设肿瘤中经PDT靶向的细胞产生的可扩散NO可能会在未靶向的旁观者细胞中引发促生长/迁移反应。在本研究中，我们使用一种新方法对此进行了测试，即在培养皿上经ALA-PDT靶向的人类癌细胞（前列腺PC3、乳腺MDA-MB-231、胶质瘤U87或黑色素瘤BLM）最初通过不可渗透的硅胶边缘环与未靶向的旁观者细胞分离。LED照射数小时后，移除环，并对两个细胞群体进行各种光照射后反应的分析。对于PDT对靶向细胞的适度且均匀的杀伤水平（约25%），旁观者的增殖和迁移均增强。增强程度与存活的靶向细胞中iNOS/NO上调的顺序相关：PC3>MDA-MB-231>U87>BLM。如果这种情况发生在实际的肿瘤PDT治疗环境中且未受到抑制（例如，通过iNOS活性或转录抑制剂），那么如果PDT的抗肿瘤效力不够强大，此类效应可能会损害治疗效果，甚至刺激疾病进展。
