Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, 56017 Pisa, Italy; Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit, 1081 HV Amsterdam, the Netherlands; Institute of Life Sciences, Sant'Anna School of Advanced Studies, 56127 Pisa, Italy.
Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, 56017 Pisa, Italy; Department of Health Sciences, University of Jaén, Campus de las Lagunillas SN, E- 23071, Jaén, Spain.
Drug Resist Updat. 2022 Sep;64:100864. doi: 10.1016/j.drup.2022.100864. Epub 2022 Sep 6.
Pancreatic ductal adenocarcinoma (PDAC) has one of the highest incidence/death ratios among all neoplasms due to its late diagnosis and dominant chemoresistance. Most PDAC patients present with an advanced disease characterized by a multifactorial, inherent and acquired resistance to current anticancer treatments. This remarkable chemoresistance has been ascribed to several PDAC features including the genetic landscape, metabolic alterations, and a heterogeneous tumor microenvironment that is characterized by dense fibrosis, and a cellular contexture including functionally distinct subclasses of cancer-associated fibroblasts, immune suppressive cells, but also a number of bacteria, shaping a specific tumor microbiome microenvironment. Thus, recent studies prompted the emergence of a new research avenue, by describing the role of the microbiome in gemcitabine resistance, while next-generation-sequencing analyses identified a specific microbiome in different tumors, including PDAC. Functionally, the contribution of these microbes to PDAC chemoresistance is only beginning to be explored. Here we provide an overview of the studies demonstrating that bacteria have the capacity to metabolically transform and hence inactivate anticancer drugs, as exemplified by the inhibition of the efficacy of 10 out of 30 chemotherapeutics by Escherichia coli. Moreover, a number of bacteria modulate specific oncogenic pathways, such as Fusobacterium nucleatum, affecting autophagy and apoptosis induction by 5-fluorouracil and oxaliplatin. We hypothesize that improved understanding of how chemoresistance is driven by bacteria could enhance the efficacy of current treatments, and discuss the potential of microbiome modulation and targeted therapeutic approaches as well as the need for more reliable models and biomarkers to translate the findings of preclinical/translational research to the clinical setting, and ultimately overcome PDAC chemoresistance, hence improving clinical outcome.
胰腺导管腺癌 (PDAC) 是所有肿瘤中发病率/死亡率最高的肿瘤之一，这是由于其诊断较晚和对化疗药物的固有耐药性。大多数 PDAC 患者表现为晚期疾病，其特征是多因素、固有和获得性对当前抗癌治疗的耐药性。这种显著的化疗耐药性归因于 PDAC 的几个特征，包括遗传景观、代谢改变以及异质性肿瘤微环境，其特征是纤维化密度增加，以及包括具有不同功能的癌症相关成纤维细胞、免疫抑制细胞等在内的细胞结构，同时还存在大量细菌，形成了特定的肿瘤微生物组微环境。因此，最近的研究通过描述微生物组在吉西他滨耐药中的作用，促使出现了一个新的研究方向，而下一代测序分析确定了不同肿瘤（包括 PDAC）中存在特定的微生物组。从功能上讲，这些微生物对 PDAC 化疗耐药性的贡献才刚刚开始被探索。在这里，我们概述了一些研究，这些研究表明细菌具有代谢转化和因此使抗癌药物失活的能力，例如大肠杆菌抑制 30 种化疗药物中的 10 种的疗效。此外，许多细菌调节特定的致癌途径，例如具核梭杆菌，影响氟尿嘧啶和奥沙利铂诱导的自噬和细胞凋亡。我们假设，更好地了解细菌如何驱动化疗耐药性可以提高现有治疗方法的疗效，并讨论微生物组调节和靶向治疗方法的潜力以及对更可靠的模型和生物标志物的需求，以将临床前/转化研究的发现转化为临床环境，并最终克服 PDAC 化疗耐药性，从而改善临床结果。
