Qorri Bessi, Mokhtari Reza Bayat, Harless William W, Szewczuk Myron R
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
ENCYT Technologies Inc., Membertou, NS B1S 0H1, Canada.
Cancers (Basel). 2022 Jul 23;14(15):3595. doi: 10.3390/cancers14153595.
Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best combination chemotherapeutic regimens. Once drug resistance develops, manifested by increased primary tumor size and new and growing metastases, patients often die rapidly from their disease. Emerging evidence indicates that chemotherapy may contribute to the development of drug resistance through the upregulation of epithelial-mesenchymal transition (EMT) pathways and subsequent cancer stem cell (CSC) enrichment. Neuraminidase-1 (Neu-1) regulates the activation of several receptor tyrosine kinases implicated in EMT induction, angiogenesis, and cellular proliferation. Here, continuous therapeutic targeting of Neu-1 using parenteral perfusion of oseltamivir phosphate (OP) and aspirin (ASA) with gemcitabine (GEM) treatment significantly disrupts tumor progression, critical compensatory signaling mechanisms, EMT program, CSC, and metastases in a preclinical mouse model of human pancreatic cancer. ASA- and OP-treated xenotumors significantly inhibited the metastatic potential when transferred into animals.
转移性胰腺癌的预后总是致命的，采用我们最佳的联合化疗方案时，估计无进展生存期的中位数约为6个月。一旦出现耐药性，表现为原发肿瘤大小增加以及新的转移灶不断出现和增大，患者通常会很快死于该疾病。新出现的证据表明，化疗可能通过上皮-间质转化（EMT）途径的上调以及随后癌症干细胞（CSC）的富集而导致耐药性的产生。神经氨酸酶-1（Neu-1）调节几种与EMT诱导、血管生成和细胞增殖有关的受体酪氨酸激酶的激活。在此，在人胰腺癌的临床前小鼠模型中，使用磷酸奥司他韦（OP）和阿司匹林（ASA）经肠胃外灌注并联合吉西他滨（GEM）治疗对Neu-1进行持续的治疗性靶向，可显著破坏肿瘤进展、关键的代偿性信号传导机制、EMT程序、CSC和转移。经ASA和OP处理的异种肿瘤在转移到动物体内时显著抑制了转移潜能。
