The contributions of sensory nerves to bone metastasis and associated bone pain
The contributions of sensory nerves to bone metastasis and associated bone pain
批准号:
10365974
负责人:
Yusuke Shiozawa
金额:
$36.9万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-03-05 至 2025-02-28
关键词:
AddressAfferent NeuronsAnimalsAreaAttenuatedBenignBiopsyBone DevelopmentBone DiseasesBone GrowthBone PainBone remodelingCalcitonin Gene-Related PeptideCalcitonin-Gene Related Peptide ReceptorCancer ControlCancer ModelCancer PatientCause of DeathCellsComplicationDataDisease ProgressionFLT3 geneFLT3 ligandGoalsGrowthHarvestImmuneImpairmentIn VitroLigandsMalignant Bone NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMarrowMeasuresMediatingMetastatic Neoplasm to the BoneMetastatic Prostate CancerMolecular ProbesMusNeoplasm MetastasisNerveNeuropeptidesPainPathway interactionsPatientsPeptide SynthesisPeptidesPeriosteumPlasmaPrimary NeoplasmPrognosisQuality of lifeRadiumRoleSchemeSpinal GangliaSymptomsSystemTissuesWorkafferent nervebonecalcitonin receptor-like receptorcancer cellcancer survivaleffective therapyganglion cellimprovedin vivoinsightmortalitymouse modelnegative affectnerve supplynew therapeutic targetnovel therapeutic interventionp38 Mitogen Activated Protein Kinasepain behaviorpain signalpalliativeprostate cancer cellprostate cancer modelprostate cancer progressionreceptorresponseskeletalsoft tissuetargeted cancer therapytreatment strategytumortumor growthtumor progression
中文摘要
项目摘要
骨转移仍然是前列腺癌患者死亡的主要原因。不幸的是,目前
骨转移的治疗主要是姑息性的。骨转移的一个主要并发症是骨痛。
尽管有多项研究表明神经在癌症进展中起作用,而骨骼
疼痛与总存活率呈负相关,其中涉及的机制仍然难以捉摸。我们发现了
这是:1)癌症转移到骨或转移性骨疾病丰富感觉神经,表达
骨内神经肽降钙素基因相关肽(CGRP),引起骨痛;2)骨转移
癌细胞表达高水平的降钙素受体样受体(CRLR);3)降钙素基因相关肽诱导癌症
通过CRLR/p38途径的增殖;4)激活的FMS样酪氨酸激酶3受体(Flt3)存在
在小鼠背根神经节出现骨痛指标;5)骨转移癌细胞表达
Flt3配体(FL)水平升高;6)FL诱导感觉神经萌发。因此,我们
假设(A)骨转移性前列腺癌来源的FL通过Flt3刺激感觉神经,
导致癌症引起的骨痛;以及(B)由癌症相关感觉神经表达的CGRP诱导
CRLR/p38通路在转移性骨疾病中的研究进展在这份R01建议书中,提交于
对PAR-16-245的反应,我们将:(1)确定骨转移癌细胞是否增加感觉神经
感觉神经的发芽和CGRP的合成,通过FL/Flt3参与癌症引起的骨痛
AXIS;以及(2)确定骨转移灶中感觉神经表达的CGRP是否刺激骨
通过CRLR/p38转移性生长。使用体外原代背根神经节培养系统和
独特的小鼠癌症引起的骨痛模型,将使我们能够在同一动物内测量:(I)肿瘤
生长,(Ii)骨骼神经,(Iii)骨骼重塑,以及(Iv)由此产生的疼痛行为。使用骨活检从
我们将探讨骨转移癌和骨转移癌之间的相互作用的分子机制。
感觉神经控制骨转移的进展和相关疼痛的发展。我们将使用
这些结果开发了一种针对癌症/神经相互作用的新治疗策略。短期内,这一点
研究将阐明骨转移和癌症引起的骨痛的新机制。从长远来看,一个更好的
了解转移进展和疼痛信号如何相互影响导致疾病恶化
进展将有助于发现癌症引起的骨痛和骨骼的新治疗靶点
转移性癌症--目前治疗方法不足的领域--减少痛苦,提高存活率
有骨转移的癌症患者。
英文摘要
Project Summary
Bone metastasis remains a major cause of death among patients with prostate cancer. Unfortunately, current
treatments for bone metastases are mainly palliative. A major complication of bone metastasis is bone pain.
Although several lines of study have suggested that nerves have a role in cancer progression, and that bone
pain and overall survival are negatively correlated, the mechanisms involved remain elusive. We have found
that: 1) cancer metastasis to bone or metastatic bone disease enriches sensory nerves that express the
neuropeptide calcitonin gene-related peptide (CGRP) in the bone, and that causes bone pain; 2) bone-metastatic
cancer cells express elevated levels of calcitonin-receptor like receptor (CRLR); 3) CGRP induces cancer
proliferation through the CRLR/p38 pathway; 4) activated FMS-like tyrosine kinase 3 receptor (Flt3) is present
in the dorsal root ganglia of mice presenting bone pain indicators; 5) bone-metastatic cancer cells express
elevated levels of the Flt3 ligand (FL); and 6) FL induces the sprouting of sensory nerves. We therefore
hypothesize that (a) FL derived from bone-metastatic prostate cancer stimulates sensory nerves through Flt3,
resulting in cancer-induced bone pain; and (b) CGRP expressed by cancer-associated sensory nerves induces
progression of metastatic bone disease through the CRLR/p38 pathway. In this R01 proposal, submitted in
response to PAR-16-245, we will: (1) Determine whether bone-metastatic cancer cells increase sensory nerve
sprouting and CGRP synthesis in sensory nerves, contributing to cancer-induced bone pain, through the FL/Flt3
axis; and (2) Determine whether CGRP expressed by sensory nerves in bone-metastatic lesions stimulate bone
metastatic outgrowth through CRLR/p38. Using an in vitro primary dorsal root ganglia culture system and a
unique mouse model of cancer-induced bone pain, will allow us to measure within the same animal: (i) tumor
growth, (ii) skeletal innervation, (iii) bone remodeling, and (iv) resultant pain behaviors. Using bone biopsies from
patients, we will probe the molecular mechanisms whereby the crosstalk between bone metastatic cancer and
sensory nerves controls both progression of bone metastases and development of associated pain. We will use
these results to develop a new therapeutic strategy targeting cancer/nerve interactions. In the short term, this
study will elucidate new mechanisms of bone metastasis and cancer-induced bone pain. In the long run, a better
understanding of how metastatic progression and pain signals influence one another to worsen disease
progression will aid in discovering new therapeutic targets for both cancer-induced bone pain and bone
metastatic cancer – areas in which current therapies are wanting – to decrease suffering and improve the survival
of cancer patients with bone metastases.
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会议论文
The contributions of sensory nerves to bone metastasis and associated bone pain
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批准号:10596199
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项目类别:
-
资助金额:$36.9万
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财政年份:2020
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负责人:Yusuke Shiozawa
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依托单位:
Mechanisms of Prostate Cancer Dormancy in the Bone Marrow Niche
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批准号:8915079
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项目类别:
-
资助金额:$83.33万
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财政年份:2011
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负责人:Yusuke Shiozawa
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依托单位:
Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
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批准号:8555280
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项目类别:
-
资助金额:$19.14万
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财政年份:2011
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负责人:Yusuke Shiozawa
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依托单位:
Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
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批准号:8713958
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项目类别:
-
资助金额:$15.48万
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财政年份:--
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负责人:Yusuke Shiozawa
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依托单位:
Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
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批准号:8567739
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项目类别:
-
资助金额:$26.89万
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财政年份:--
-
负责人:Yusuke Shiozawa
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依托单位:
Identifying Circulating Tumor Cells that Become Dormant Disseminated Tumor Cells
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批准号:8915090
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项目类别:
-
资助金额:$26.04万
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财政年份:--
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负责人:Yusuke Shiozawa
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依托单位:
海外基金