Am J Cancer Res. 2011;1(7):834-44. Epub 2011 Aug 18.
Prostate cancer remains the most common noncutaneous cancer among American men. Although most patients can be cured by surgery and radiotherapy, 32,050 patients still died of the disease in 2010. Many patients receive radiotherapy either as a primary therapy, salvage therapy, or in combination with surgery or hormonal therapy. Despite initial treatment, several studies suggest that approximately 10% of low-risk prostate cancer patients and up to 30-60% with more advanced cancer patients experience biochemical recurrence within five years after radiotherapy. Thus, elucidating the molecular mechanisms underlying radioresistance and tumor recurrence has the potential to significantly reduce prostate cancer mortality. We previously demonstrated that fractionated ionizing radiation (IR) can induce the prostate cancer cell line LNCaP to undergo neuroendocrine differentiation (NED) by activation of cAMP response element binding protein (CREB) and cytoplasmic sequestration of ATF2, two CRE-binding transcription factors that oppose each other to regulate NED. Importantly, IR-induced NED is reversible and de-differentiated cells are cross-resistant to IR, androgen depletion and docetaxel treatments. These findings suggest that radiation-induced NED may allow prostate cancer cells to survive treatment and contribute to tumor recurrence. In the present study, we further demonstrated that IR also induces NED in a subset of DU-145 and PC-3 cells. In addition, we confirmed that IR induces NED in LNCaP xenograft tumors in nude mice, and observed that the plasma chro-mogranin A (CgA) level, a biomarker for NED, is increased by 2- to 5-fold in tumor-bearing mice after fractionated radiation doses of 20 and 40 Gy, respectively. Consistent with these in vivo findings, a pilot study in prostate cancer patients showed that the serum CgA level is elevated in 4 out of 9 patients after radiotherapy. Taken together, these findings provide evidence that radiation-induced NED is a general therapeutic response in a subset of prostate cancer patients. Thus, a large scale analysis of radiotherapy-induced NED in prostate cancer patients and its correlation to clinical outcomes will likely provide new insight into the role of NED in prostate cancer radiotherapy and prognosis.
前列腺癌仍然是美国男性中最常见的非皮肤癌。尽管大多数患者可以通过手术和放疗治愈，但 2010 年仍有 32050 名患者死于该病。许多患者接受放疗，无论是作为主要治疗、挽救性治疗，还是与手术或激素治疗联合使用。尽管进行了初始治疗，但多项研究表明，大约 10%的低危前列腺癌患者和约 30-60%的癌症进展患者在放疗后五年内出现生化复发。因此，阐明放射抵抗和肿瘤复发的分子机制有可能显著降低前列腺癌的死亡率。我们之前的研究表明，分次电离辐射（IR）可以通过激活 cAMP 反应元件结合蛋白（CREB）和 ATF2 的细胞质隔离来诱导前列腺癌细胞系 LNCaP 发生神经内分泌分化（NED），ATF2 是两种相反的 CRE 结合转录因子，用于调节 NED。重要的是，IR 诱导的 NED 是可逆的，去分化细胞对 IR、雄激素剥夺和多西他赛治疗具有交叉耐药性。这些发现表明，放射诱导的 NED 可能使前列腺癌细胞能够在治疗中存活下来，并导致肿瘤复发。在本研究中，我们进一步证明，IR 也诱导了 DU-145 和 PC-3 细胞中的一部分发生 NED。此外，我们证实 IR 诱导了裸鼠 LNCaP 异种移植肿瘤中的 NED，并观察到，在接受 20 和 40 Gy 分次照射剂量后，荷瘤小鼠的血浆嗜铬粒蛋白 A（CgA）水平分别增加了 2 至 5 倍。与这些体内发现一致，对 9 名前列腺癌患者的一项初步研究表明，在放疗后，4 名患者的血清 CgA 水平升高。总之，这些发现提供了证据表明，放射诱导的 NED 是一部分前列腺癌患者的普遍治疗反应。因此，对前列腺癌患者放疗诱导的 NED 及其与临床结果的相关性进行大规模分析，可能会为 NED 在前列腺癌放疗和预后中的作用提供新的见解。
