Prox Daniela, Becker Christian, Pirie-Shepherd Steven R, Celik Ilhan, Folkman Judah, Kisker Oliver
Division of Surgical Research, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
World J Surg. 2003 Apr;27(4):405-11. doi: 10.1007/s00268-002-6816-4.
Tumor growth is dependent on the balance of positive and negative regulators of angiogenesis. Antiangiogenic compounds inhibit endothelial cell biology in vitro and angiogenesis in vivo. Therefore antiangiogenic therapy presumes to be an effective treatment for pancreatic cancer. We wanted to determine the effect of antiangiogenic therapy on the growth of human pancreatic cancer in a mouse model. The angiogenesis inhibitors TNP-470 and antiangiogenic antithrombin III (aaATIII) were tested in vitro for their ability to inhibit endothelial cell proliferation. These inhibitors, along with the known antiangiogenic molecule endostatin, were then employed to treat two different primary human pancreatic cancers implanted subcutaneously into the dorsa of immunodeficient (SCID) mice. Treated tumors were examined histologically for microvessel density, apoptosis, and proliferation. All three inhibitors suppressed the growth of pancreatic tumors in vivo. Immunohistochemical analysis revealed increased degrees of apoptosis and reduced microvessel density in treated tumors compared to untreated tumors, although tumor cell proliferation was the same in both groups. None of the inhibitors tested significantly inhibited proliferation of human pancreatic cancer cells, although both TNP-470 and aaATIII were able to inhibit the proliferation of endothelial cells. The observed tumor suppression may be due to increased tumor cell apoptosis as a result of capillary dropout. These studies show that after the angiogenic switch in a human tumor, there is residual production of angiogenesis inhibitors.
肿瘤生长取决于血管生成正负调节因子之间的平衡。抗血管生成化合物在体外可抑制内皮细胞生物学行为，在体内可抑制血管生成。因此，抗血管生成疗法被认为是治疗胰腺癌的一种有效方法。我们想在小鼠模型中确定抗血管生成疗法对人胰腺癌生长的影响。在体外测试了血管生成抑制剂TNP - 470和抗血管生成抗凝血酶III（aaATIII）抑制内皮细胞增殖的能力。然后，将这些抑制剂与已知的抗血管生成分子内皮抑素一起用于治疗皮下植入免疫缺陷（SCID）小鼠背部的两种不同的原发性人胰腺癌。对治疗后的肿瘤进行组织学检查，以检测微血管密度、细胞凋亡和增殖情况。所有三种抑制剂在体内均抑制了胰腺肿瘤的生长。免疫组织化学分析显示，与未治疗的肿瘤相比，治疗后的肿瘤细胞凋亡程度增加，微血管密度降低，尽管两组的肿瘤细胞增殖情况相同。所测试的抑制剂均未显著抑制人胰腺癌细胞的增殖，尽管TNP - 470和aaATIII都能够抑制内皮细胞的增殖。观察到的肿瘤抑制可能是由于毛细血管缺失导致肿瘤细胞凋亡增加所致。这些研究表明，在人类肿瘤发生血管生成转换后，仍有血管生成抑制剂的残留产生。
