Background:Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively.Methods:Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics.Results:We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized13C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts.Conclusion:While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized13C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted)1H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response.
背景：强效雄激素受体通路抑制剂会诱导产生小细胞神经内分泌前列腺癌（SCNC），这是一种高度侵袭性的转移性去势抵抗性前列腺癌（ARPC）亚型，其治疗选择有限且生存率较低。相较于仅有骨转移的患者，发生肝转移的患者预后更差。ARPC在骨骼与肝脏中表现出不同生物学行为的机制可能涉及肿瘤细胞内在因素、肿瘤微环境和/或全身性因素，识别这些因素对于改善SCNC的诊断和治疗至关重要。代谢重编程是肿瘤细胞在不同于原发部位的微环境中定植和增殖的基本策略。理解癌细胞的代谢可塑性可能为更有效地成像和治疗转移灶提供新方法。 方法：通过磁共振（MR）成像与波谱技术，我们研究了在骨骼和肝脏中传代培养的SCNC患者来源异种移植瘤（PDXs）的生理与代谢特征，并利用相关生化、免疫组化及转录组学检测手段，以理解所观察到的影像学指标背后的生物学基础。 结果：我们发现，微环境对PDXs模型生理学指标（通过MRI测量）的影响存在差异。然而，利用超极化13C丙酮酸通过MR测量的肝脏糖酵解能力，重现了酶活性（乳酸脱氢酶）、辅因子（烟酰胺腺嘌呤二核苷酸）以及乳酸分数富集度的稳定同位素测量结果。而在骨骼中，糖酵解成分的一致性丧失，且可能受到癌细胞与破骨细胞/成骨细胞相互作用的权重影响。 结论：尽管微环境因素对代谢影响甚微，但生理学指标（细胞密度与灌注）具有高度变异性，因此需要结合使用超极化13C MRI和多参数（解剖、扩散及灌注加权）1H MRI来更好地表征治疗前的肿瘤特征，这对于评估治疗反应至关重要。
肿瘤(癌症)患者之家