ROLE OF THE UROKINASE RECEPTOR IN INVASIVE COLON CANCER
ROLE OF THE UROKINASE RECEPTOR IN INVASIVE COLON CANCER
批准号:
2099003
负责人:
Douglas D. Boyd
金额:
$13.75万
依托单位国家:
美国
项目类别:
财政年份:
1994
资助国家:
美国
项目状态:
已结题
起止时间:
1994-07-01 至 1997-06-30
中文摘要
结肠癌患者的高死亡率总是反映了
将疾病扩散到次要器官。 的理解
强调疾病这一阶段的机制最终可能,
从而导致旨在对抗肿瘤扩散的治疗策略。 的
肿瘤细胞降解周围细胞外基质的能力,
通过水解机制,代表了
转移 纤溶酶原激活剂(PA),尿激酶(u-PA),已被
通过其将惰性蛋白质转化为肿瘤细胞的能力而参与肿瘤细胞侵袭。
纤溶酶原转化为丝氨酸蛋白酶纤溶酶,
包括层粘连蛋白和IV型胶原蛋白。u-PA
可以与细胞上的特定受体结合,而这种受体不会降低-
调节,从而在肿瘤细胞表面集中PA。
受体结合型u-PA激活纤溶酶原的速度比液体快,
相u-PA。 在具体目标#1中,该结合位点在体外的作用
并且体内侵袭将通过基因横切研究来确定,
通过利用与细胞表面竞争的可溶性受体
u-PA结合的受体。 多项研究表明,
u-PA抑制剂可抑制液相纤溶酶原激活剂。
然而,受体结合u-PA对这些抑制剂的敏感性
目前还不清楚。 在具体目标#2中,
内源性u-PA抑制剂阻断受体-
将测定结合的u-PA对结肠癌的作用。 如果确实是u-PA
受体是u-PA依赖性蛋白水解的关键决定因素,
入侵,了解其表达的调控,
最终,导致开发新的化合物,
显示这些结合位点,并因此损害
结肠肿瘤细胞的侵袭能力。 在具体目标#3中,
蛋白激酶C途径在u-PA受体调节中的作用
表达将被确定。 在具体目标#4中,
哪种蛋白激酶C途径刺激u-PA受体表达
要有决心。临床观察显示20%的淋巴结-
阴性患者会出现疾病复发。的识别
该组患者将合理化辅助治疗,
目前仅限于淋巴结阳性患者。
相反,40%的淋巴结阳性患者通过手术治愈
然而,由于没有足够的药物,
这是一种识别患者主体的方法。 在具体目标#5中,
将确定u-PA受体水平是否是疾病的预测因子
结肠癌患者的复发。
英文摘要
High mortality rates in patients with colon cancer invariably reflect the
spread of the disease to secondary organs. An understanding of the
mechanisms which underscore this phase of the disease could ultimately,
lead to therapeutic strategies aimed at combating tumor spread. The
ability of tumor cells to degrade the surrounding extracellular matrix,
via hydrolytic mechanisms, represents one of the first steps of
metastasis. The plasminogen activator (PA), urokinase, (u-PA), has been
implicated in tumor cell invasion via its ability to convert the inert
plasminogen into the serine protease plasmin which cleaves key components
of the extracellular matrix including laminin and type IV collagen. u-PA
can be bound to a specific receptor on the cell, which does not down-
regulated, thus concentrating the PA at the tumor cell surface.
Receptor-bound u-PA activates plasminogen at a faster rate than fluid-
phase u-PA. In specific Aim #1 the role of this binding site in vitro
and in vivo invasion will be determined by gene transection studies and
by making use of a soluble receptor which competes with cell surface
receptors for u-PA binding. Several studies have shown that endogenous
u-PA inhibitors can inhibit the fluid-phase plasminogen activator.
However, the susceptibility of receptor-bound u-PA to these inhibitors
is unclear at the present time. In Specific Aim #2 the role of
endogenous u-PA inhibitor in blocking plasminogen activation by receptor-
bound u-PA on colon cancer will be determined. If indeed the u-PA
receptor is a critical determinant of u-PA-dependent proteolysis and
invasion, an understanding of the regulation of its expression could,
ultimately, lead to the development of novel compounds which decrease the
display of these binding sites and which, consequently, impair the
invasive capacity of colonic tumor cells. In Specific Aim #3, the role
of Protein Kinase C pathways in the regulation of u-PA receptors
expression will be determined. In Specific Aim #4, the mechanism by
which Protein Kinase C pathways stimulate u-PA receptors expression will
be determine. Clinical observations indicated the 20% of lymph node -
negative patients will have disease recurrence. The identification of
patients within this group would rationalize adjuvant therapy, which at
eh present time, is restricted to lymph node-positive patients.
Conversely, 40% of lymph node-positive patients are cured with surgery
yet undergo costly debilitating chemotherapy since there is no adequate
means of identifying this subject of patients. In Specific Aim #5, we
will determine if u-PA receptor levels is a predictor of disease
recurrence in colon cancer patients.
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会议论文
Src requirement for u-PAR expression by HGF and hypoxia
-
批准号:6922046
-
项目类别:
-
资助金额:$25.1万
-
财政年份:2003
-
负责人:Douglas D. Boyd
-
依托单位:
Src requirement for u-PAR expression by HGF and hypoxia
-
批准号:6739102
-
项目类别:
-
资助金额:$25.1万
-
财政年份:2003
-
负责人:Douglas D. Boyd
-
依托单位:
Src requirement for u-PAR expression by HGF and hypoxia
-
批准号:6575882
-
项目类别:
-
资助金额:$25.1万
-
财政年份:2003
-
负责人:Douglas D. Boyd
-
依托单位:
UROKINASE RECEPTOR EXPRESSION--COLON CANCER
-
批准号:6171928
-
项目类别:
-
资助金额:$19.76万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of urokinase receptor expression in colon CA
-
批准号:6607838
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of urokinase receptor expression in colon CA
-
批准号:7058227
-
项目类别:
-
资助金额:$25.8万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of urokinase receptor expression in colon cancer
-
批准号:7866600
-
项目类别:
-
资助金额:$26.32万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
ROLE OF THE UROKINASE RECEPTOR IN INVASIVE COLON CANCER
-
批准号:2099004
-
项目类别:
-
资助金额:$14.3万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
PROTEASE EXPRESSION IN ORAL CANCER
-
批准号:6150523
-
项目类别:
-
资助金额:$19.13万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
PROTEASE EXPRESSION IN ORAL CANCER
-
批准号:2872151
-
项目类别:
-
资助金额:$18.57万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
PROTEASE EXPRESSION IN ORAL CANCER
-
批准号:6350581
-
项目类别:
-
资助金额:$19.7万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
IMPORTANCE OF EXPRESSION OF PROTEASES IN ORAL CANCER
-
批准号:2131743
-
项目类别:
-
资助金额:$13.13万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of type IV collagenase expression
-
批准号:6984074
-
项目类别:
-
资助金额:$25.8万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of urokinase receptor expression in colon cancer
-
批准号:7231429
-
项目类别:
-
资助金额:$25.06万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of urokinase receptor expression in colon cancer
-
批准号:7622899
-
项目类别:
-
资助金额:$28.76万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
UROKINASE RECEPTOR EXPRESSION--COLON CANCER
-
批准号:2894991
-
项目类别:
-
资助金额:$19.18万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
UROKINASE RECEPTOR EXPRESSION--COLON CANCER
-
批准号:2700491
-
项目类别:
-
资助金额:$18.62万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
UROKINASE RECEPTOR EXPRESSION--COLON CANCER
-
批准号:6375960
-
项目类别:
-
资助金额:$20.35万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
UROKINASE RECEPTOR EXPRESSION--COLON CANCER
-
批准号:2393435
-
项目类别:
-
资助金额:$18.08万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
Regulation of type IV collagenase expression
-
批准号:6697328
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1994
-
负责人:Douglas D. Boyd
-
依托单位:
海外基金