Endothelial Transdifferentiation of Invasive Tumor Cells

侵袭性肿瘤细胞的内皮转分化

• 批准号: 8058618
• 负责人: MARY J.C. HENDRIX
• 金额: $ 38.21万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058618
• 关键词: 3-Dimensional; Animal Model; Blood Vessels; Blood capillaries; Data; Embryo; Embryonic Development; Endothelial Cells; Extracellular Matrix; Funding; Genotype; Human; In Situ; Ischemia; Limb structure; Melanoma Cell; Modeling; Molecular; Molecular Profiling; Patients; Pattern; Phenotype; Stem cells; Structure; Tissues; Tubular formation; Wound Healing; angiogenesis; cadherin 5; capillary; clinical Diagnosis; melanoma; mimicry; molecular marker; neoplastic cell; novel; outcome forecast; transdifferentiation; tumor; vasculogenesis

DESCRIPTION (provided by applicant): During embryonic development, the formation of primary vascular networks occurs by vasculogenesis -- the in situ differentiation of progenitor cells to endothelial cells that organize into a primitive network. The subsequent remodeling of the vasculogenic network into a functionally efficient vasculature occurs through angiogenesis -- the sprouting of new capillaries from a preexisting network. We have introduced the term "vasculogenic mimicry" to describe the unique ability of aggressive melanoma tumor cells to form tubular structures and patterned networks in 3-D culture, which "mimics" the pattern of embryonic vasculogenic networks and recapitulates the patterned networks seen in patients' aggressive tumors -- correlating with poor prognosis. The molecular profile of these aggressive tumor cells suggests that they have a deregulated genotype, capable of expressing an endothelial-like phenotype. Our preliminary studies indicate that: 1) aggressive melanoma cells express VE-cadherin (exclusively expressed by endothelial cells); 2) aggressive tumor cells produce an extracellular matrix (ECM) that induces poorly aggressive melanoma cells to form vasculogenic networks; and 3) aggressive melanoma cells participate in the revascularization of an ischemic limb model, thus illustrating their endothelial stem cell plasticity. The proposed studies advance observations made during the current funding period regarding the embryonic-like phenotype of aggressive melanoma cells: Aim 1: Determine the functional significance of VE-cadherin expression in human melanoma tumor cells engaged in endothelial transdifferentiation and vasculogenic mimicry. Aim 2: Identify the key molecular components produced by aggressive melanoma tumor cells that induce poorly aggressive melanoma cells to form vasculogenic networks and mimic endothelial cells. Aim 3: Investigate the stem cell plasticity of aggressive melanoma tumor cells for their potential to re-vascularize tissues in animal models of wound healing and ischemia. The data generated from these novel studies will provide new molecular markers for clinical diagnosis and new concepts regarding the trarisendothelial differentiation of aggressive melanoma tumor cells and their stem cell plasticity.

描述（由申请人提供）：在胚胎发育期间， 初级血管网的形成是通过血管发生--原位的 祖细胞向内皮细胞的分化， 原始网络随后的血管生成网络重塑成一个 功能有效的脉管系统通过血管生成发生-- 新的毛细血管从一个预先存在的网络。我们引入了这个术语 “血管生成拟态”来描述侵袭性黑色素瘤的独特能力 肿瘤细胞在3-D培养中形成管状结构和图案化网络， 它“模仿”胚胎血管生成网络的模式， 在患者的侵袭性肿瘤中看到的模式化网络--与 预后不良。这些侵袭性肿瘤细胞的分子特征表明 他们有一个失调的基因型，能够表达一个 内皮样表型。我们的初步研究表明：1） 侵袭性黑色素瘤细胞表达VE-钙粘蛋白（仅由 2）侵袭性肿瘤细胞产生细胞外基质 (ECM)它能诱导侵袭性差的黑色素瘤细胞形成血管生成细胞， 网络;和3）侵袭性黑色素瘤细胞参与血管重建 缺血肢体模型，从而说明他们的内皮干细胞 可塑性拟议的研究推进了当前期间的观察， 关于侵袭性黑色素瘤胚胎样表型的资助期 目的1：确定VE-钙粘蛋白表达的功能意义 在参与内皮转分化的人黑素瘤肿瘤细胞中， 血管生成拟态目的2：确定由以下物质产生的关键分子组分： 侵袭性黑色素瘤肿瘤细胞诱导侵袭性差的黑色素瘤细胞， 形成血管生成网络并模仿内皮细胞。目标3：调查 侵袭性黑色素瘤肿瘤细胞干细胞可塑性， 在伤口愈合和局部缺血的动物模型中使组织再血管化。数据 这些新的研究产生的新的分子标记将提供新的分子标记， 临床诊断和新的概念，关于血管内皮细胞 侵袭性黑色素瘤肿瘤细胞及其干细胞的分化 可塑性

项目成果

Tumor cell vascular mimicry: Novel targeting opportunity in melanoma.

• DOI: 10.1016/j.pharmthera.2016.01.006
• 发表时间: 2016-03
• 期刊: Pharmacology & therapeutics
• 影响因子: 13.5
• 作者: Hendrix MJ;Seftor EA;Seftor RE;Chao JT;Chien DS;Chu YW
• 通讯作者: Chu YW

New Anti-Nodal Monoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1 Binding.

针对涉及Cripto-1结合的淋巴结前环路的新的抗鼻单克隆抗体。

• DOI: 10.3390/ijms160921342
• 发表时间: 2015-09-07
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Focà A;Sanguigno L;Focà G;Strizzi L;Iannitti R;Palumbo R;Hendrix MJ;Leonardi A;Ruvo M;Sandomenico A
• 通讯作者: Sandomenico A

Putative multifunctional signature of lung metastases in dedifferentiated chondrosarcoma.

• DOI: 10.1155/2012/820254
• 发表时间: 2012
• 期刊: Sarcoma
• 作者: Malchenko S;Seftor EA;Nikolsky Y;Hasegawa SL;Kuo S;Stevens JW;Poyarkov S;Nikolskaya T;Kucaba T;Wang M;Abdulkawy H;Casavant T;Morcuende J;Buckwalter J;Hohl R;Deyoung B;Kernstine K;Bonaldo Mde F;Hendrix MJ;Soares MB;Soares VM
• 通讯作者: Soares VM

Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype.

• DOI: 10.1158/0008-5472.can-10-0705
• 发表时间: 2010-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hardy KM;Kirschmann DA;Seftor EA;Margaryan NV;Postovit LM;Strizzi L;Hendrix MJ
• 通讯作者: Hendrix MJ

Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.

• DOI: 10.1158/1541-7786.mcr-14-0077
• 发表时间: 2015-04
• 期刊: Molecular cancer research : MCR
• 作者: Hardy KM;Strizzi L;Margaryan NV;Gupta K;Murphy GF;Scolyer RA;Hendrix MJ
• 通讯作者: Hendrix MJ