Hobbs Jennifer E, Zakarija Anaadriana, Cundiff Deborah L, Doll Jennifer A, Hymen Emily, Cornwell Mona, Crawford Susan E, Liu Na, Signaevsky Maxim, Soff Gerald A
The Division of Hematology/Oncology of the Feinberg School of Medicine at Northwestern University, Chicago, IL, USA.
Thromb Res. 2007;120 Suppl 2:S13-21. doi: 10.1016/S0049-3848(07)70126-3.
Tissue Factor (TF) expression is observed in many types of cancer, associated with more aggressive disease, and thrombosis. Alternatively-spliced human tissue factor (asHTF) has recently been identified in which exon 5 is deleted. asHTF is soluble due to the substitution of the transmembrane and cytoplasmic domains of exon 6 with a unique COOH-terminal domain.
We examine the expression and function of asHTF and full-length Tissue Factor ((FL)TF) in six human pancreatic cancer cells. Further, we transfected asHTF, (FL)TF, and control expression vectors into a non-expressing, human pancreatic cancer line (MiaPaCa-2). We studied the procoagulant activity of asHTF and (FL)TF and the effect on tumor growth in mice.
asHTF is expressed in 5 of 6 human pancreatic cancer cell lines, but not in normal human fibroblasts, nor the MiaPaCa-2 line. (FL)TF conferred procoagulant activity, but asHTF did not. Transfected cells were injected subcutaneously in athymic mice. Interestingly, compared with control transfection, (FL)TF expression was associated with reduced tumor growth (mean 7 mg vs 85 mg), while asHTF-expression was associated with enhanced tumor growth (mean 389 mg vs. 85 mg). asHTF expression resulted in increased mitotic index and microvascular density.
These data suggests that asHTF expression promotes tumor growth, and is associated with increased tumor cell proliferation and angiogenesis in vivo. Our results raise a new perspective on the understanding of the relationship between TF expression and cancer growth, by showing a dissociation of the procoagulant activity of (FL)TF and the cancer-promoting activity of asHTF.
在多种癌症类型中均观察到组织因子（TF）的表达，其与更具侵袭性的疾病及血栓形成相关。最近发现了选择性剪接的人组织因子（asHTF），其中外显子5缺失。由于外显子6的跨膜和胞质结构域被独特的COOH末端结构域取代，asHTF是可溶的。
我们检测了asHTF和全长组织因子（(FL)TF）在六种人胰腺癌细胞中的表达及功能。此外，我们将asHTF、(FL)TF及对照表达载体转染至一个不表达的人胰腺癌系（MiaPaCa-2）中。我们研究了asHTF和(FL)TF的促凝血活性以及对小鼠肿瘤生长的影响。
asHTF在6种人胰腺癌细胞系中的5种中表达，但在正常人成纤维细胞及MiaPaCa-2细胞系中不表达。(FL)TF具有促凝血活性，但asHTF没有。将转染细胞皮下注射到无胸腺小鼠体内。有趣的是，与对照转染相比，(FL)TF表达与肿瘤生长减缓相关（平均7毫克对85毫克），而asHTF表达与肿瘤生长增强相关（平均389毫克对85毫克）。asHTF表达导致有丝分裂指数和微血管密度增加。
这些数据表明asHTF表达促进肿瘤生长，并与体内肿瘤细胞增殖和血管生成增加相关。我们的结果通过显示(FL)TF的促凝血活性与asHTF的促癌活性的分离，为理解TF表达与癌症生长之间的关系提出了新的视角。
