There is a growing interest in exploring the therapeutically mediated modulation of tumor vascularization of pancreatic cancer, which is known for its poorly perfused tumor microenvironment limiting the delivery of therapeutic agents to the tumor site. Here, we assessed how magnetic hyperthermia in combination with chemotherapy selectively affects growth, the vascular compartment of tumors, and the presence of tumor cells expressing key regulators of angiogenesis. To that purpose, a orthotopic PANC-1 (fluorescent human pancreatic adenocarcinoma) mouse tumor model (Rj:Athym-Foxn1nu/nu) was used. Magnetic hyperthermia was applied alone or in combination with systemic chemotherapy (gemcitabine 50 mg per kg body weight, nab-pacitaxel 30 mg/kg body weight) on days 1 and 7 following magnetic nanoparticle application (dose: 1 mg per 100 mm3of tumor). We used ultrasound imaging, immunohistochemistry, multi-spectral optoacoustic tomography (MSOT), and hematology to assess the biological parameters mentioned above. We found that magnetic hyperthermia in combination with gemcitabine/paclitaxel chemotherapy was able to impact tumor growth (decreased volumes and Ki67 expression) and to trigger neo-angiogenesis (increased small vessel diameter) as a result of the therapeutically mediated cell damages/stress in tumors. The applied stressors activated specific pro-angiogenic mechanisms, which differed from those seen in hypoxic conditions involving HIF-1α, since (a) treated tumors showed a significant decrease of cells expressing VEGF, CD31, HIF-1α, and neuropilin-1; and (b) the relative tumor blood volume and oxygen level remained unchanged. Neo-angiogenesis seems to be the result of the activation of cell stress pathways, like MAPK pathways (high number of pERK-expressing tumor cells). In the long term, the combination of magnetic hyperthermia and chemotherapy could potentially be applied to transiently modulate tumor angiogenesis and to improve drug accessibility during oncologic therapies of pancreatic cancer.
胰腺癌因其肿瘤微环境灌注不良而限制治疗药物递送至病灶，对肿瘤血管化进行治疗性调控的研究日益受到关注。本研究通过建立原位PANC-1（荧光标记人胰腺腺癌）小鼠肿瘤模型（Rj:Athym-Foxn1nu/nu），评估磁热疗联合化疗如何选择性影响肿瘤生长、血管结构及表达血管生成关键调节因子的肿瘤细胞。在磁性纳米颗粒注射（剂量：1mg/100mm³肿瘤体积）后第1天和第7天，分别实施单独磁热疗或联合系统化疗（吉西他滨50mg/kg体重，白蛋白结合型紫杉醇30mg/kg体重）。采用超声成像、免疫组化、多光谱光声断层扫描（MSOT）及血液学检测评估上述生物学参数。研究发现：磁热疗联合吉西他滨/紫杉醇化疗通过介导肿瘤细胞损伤/应激，能够抑制肿瘤生长（体积减小及Ki67表达降低）并触发新生血管生成（小血管直径增加）。该治疗激活的促血管生成机制与缺氧条件下HIF-1α介导的途径存在差异，表现为：（a）治疗组肿瘤表达VEGF、CD31、HIF-1α和神经纤毛蛋白-1的细胞显著减少；（b）肿瘤相对血容量及氧水平维持不变。新生血管生成可能是细胞应激通路（如MAPK通路）激活的结果，表现为大量肿瘤细胞表达pERK。长期来看，磁热疗联合化疗有望在胰腺癌治疗中实现肿瘤血管的短暂调控，从而提升药物治疗可及性。
肿瘤(癌症)患者之家