Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
批准号:
8915090
负责人:
Yusuke Shiozawa
金额:
$26.04万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
已结题
起止时间:
至 2017-07-31
关键词:
AddressAffectAgarAnimalsAnnexinsAntibodiesBindingBiological AssayBloodBone MarrowCXCR4 geneCancer PatientCell CycleCellsClinicalDiseaseDistantEngraftmentEventFrequenciesGene Expression ProfilingGrowthHLA AntigensHematopoietic stem cellsHomingHoming BehaviorHumanImmuneImplantIntegrinsInterleukin-6InvestigationLaboratory ResearchLeadLinkMalignant NeoplasmsMalignant neoplasm of prostateMarrowMetastatic Prostate CancerModelingMolecularMorbidity - disease rateMusNeoplasm Circulating CellsNeoplasm MetastasisOsteoblastsPhenotypePopulationPositioning AttributeRelapseResistanceSeedsSignal PathwaySignal TransductionSiteSoilStem cellsTechnologyTimeTissuesTransplantationWorkXenograft Modelaldehyde dehydrogenasesbasecell behaviorclinically relevantfallsgenetic approachin vivoinsightmetastatic processmortalityneoplastic cellpreventprostate cancer cellprostate cancer cell linereceptorresponsestem cell nichetumorigenicvertebra body
中文摘要
从原发肿瘤脱落的播散性肿瘤细胞(dtc)可能在远处组织中潜伏很长时间
英文摘要
Disseminated tumor cells (DTCs) shed from a primary tumor may lie dormant in distant tissues for long
periods of time before they can be activated to form metastases. Recently work in our group has shown that
(i) the engraftment of hematopoietic stem cells (HSC) and (ii) prostate cancer (PCa) metastasis to the
marrow are dependent on many of the same molecules. In fact, we have recently demonstrated that
metastatic PCa directly competes with HSC for occupancy of the niche. We have also developed technology
and models that permits isolation of human DTCs from marrow using anti-human leukocyte antigens (HLA).
Hypothesis: Molecules that induce HSC dormancy also induce dormancy of metastatic PCa cells and
can be used to identify DTCs.
The following aims are proposed:
(1) Identify the differences between circulating tumor cells (CTCs) and successful DTCs.
Sub Hypothesis: Dormant DTCs have different profiles from CTCs and dividing DTCs.
We will determine the expression levels of receptors, known to regulate homing, lodging and growth, and
gene expression profiling on CTCs and DTCs that will be obtained from our murine xenograft model. Then,
these analyses will be repeated with CTCs and DTCs obtained from PCa patients.
(2) Identify the specific subtype of DTCs that become dormant.
Sub hypotheses: DTCs that become dormant have the capability to eventually form tumors.
First, we will determine the frequency of tumorigenic cells in the dormant DTCs by implanting into
immunocompromized mice. Next, we will determine the tumorogenic phenotype while determining if these
cells also have the colony-forming ability and chemo-resistant ability. Finally, we will determine if we can
manipulate dormant state of these cells with GAS6 (See Project 2) or IL-6 (See Project 3).
(3) Determine the molecular mechanism that is critical for DTCs to become dormant.
Sub hypotheses: The binding to annexin 2 (AnxaZ) is critical for DTCs to become dormant
We have demonstrated that Anxa2 expressed by osteoblasts is a crucial molecule for the niche selection of
PCa, This suggests that PCa obtain the signals from the niche through the Anxa2/Anxa2r axis. Therefore,
we will determine if blocking Anxa2r on PCa prevents becoming dormant. In addition, we have observed
that when PCa bind to Anxa2, the expression of Axl, the receptors for GAS6, is enhanced on the PCa. Thus,
we will determine signaling pathway that is involved in the effects of Anxa2 on Axl induction.
These findings will directly lend support to Project 2 which will determine how endosteal HSC niche regulates
tumor dormancy, and Project 3 which focuses on what leads to activation of the dormant cells.
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财政年份:2020
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资助金额:$26.89万
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Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
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资助金额:$15.48万
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财政年份:--
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依托单位:
海外基金