Djokovic Dusan, Trindade Alexandre, Gigante Joana, Pinho Mario, Harris Adrian L, Duarte Antonio
Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal.
Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
BMC Cancer. 2015 Aug 28;15:608. doi: 10.1186/s12885-015-1605-2.
In invasive malignancies, Dll4/Notch signaling inhibition enhances non-functional vessel proliferation and limits tumor growth by reducing its blood perfusion.
To assess the effects of targeted Dll4 allelic deletion in the incipient stages of tumor pathogenesis, we chemically induced skin papillomas in wild-type and Dll4 (+/-) littermates, and compared tumor growth, their histological features, vascularization and the expression of angiogenesis-related molecules.
We observed that Dll4 down-regulation promotes productive angiogenesis, although with less mature vessels, in chemically-induced pre-cancerous skin papillomas stimulating their growth. The increase in endothelial activation was associated with an increase in the VEGFR2 to VEGFR1 ratio, which neutralized the tumor-suppressive effect of VEGFR-targeting sorafenib. Thus, in early papillomas, lower levels of Dll4 increase vascularization through raised VEGFR2 levels, enhancing sensitivity to endogenous levels of VEGF, promoting functional angiogenesis and tumor growth.
Tumor promoting effect of low-dosage inhibition needs to be considered when implementing Dll4 targeting therapies.
在侵袭性恶性肿瘤中，Dll4/Notch信号通路抑制可增强无功能血管增殖，并通过减少肿瘤血供来限制肿瘤生长。
为评估在肿瘤发病初期靶向Dll4等位基因缺失的影响，我们在野生型和Dll4（+/-）同窝小鼠中化学诱导皮肤乳头状瘤，并比较肿瘤生长、组织学特征、血管生成以及血管生成相关分子的表达。
我们观察到，在化学诱导的癌前皮肤乳头状瘤中，Dll4下调促进了有功能的血管生成，尽管血管不太成熟，从而刺激了肿瘤生长。内皮细胞激活增加与VEGFR2与VEGFR1比值增加有关，这抵消了靶向VEGFR的索拉非尼的肿瘤抑制作用。因此，在早期乳头状瘤中，较低水平的Dll4通过提高VEGFR2水平增加血管生成，增强对内源性VEGF水平的敏感性，促进有功能的血管生成和肿瘤生长。
在实施Dll4靶向治疗时，需要考虑低剂量抑制的促肿瘤作用。
