Role of HSP70 in Pancreatic Diseases

摘要 几种保护机制已经进化出来，以确保细胞在不利条件下存活。‘热 “休克反应”就是这样一种生存机制。我们之前已经证明了热休克蛋白-70，一种 多面伴侣蛋白在急性胰腺炎期间保护胰腺腺泡细胞免受损伤。我们 已经将这些观察扩展到胰腺癌，并证明(HSP70)是 在胰腺癌细胞中过表达，并在保护癌细胞免受细胞伤害方面起着非常显著的作用 死亡。 虽然之前的研究主要集中在癌细胞的特性上，但最近有 增加对肿瘤微环境(TME)在支持癌症生长中的作用的了解。 胰腺癌有复杂的TME，这被认为是导致其侵袭性行为的原因。而当 对非胰腺肿瘤的研究表明，间质中缺乏热休克因子-1(HSF1)会降低 热休克反应通路在胰腺癌TME形成中的作用 学习。 有趣的是，我们的数据表明，雷公藤甲素，一种天然的热休克抑制剂，调节胰腺癌 刺激和消耗间质。我们的初步数据还表明，基质细胞中缺乏HSP70是 与细胞毒性T细胞浸润增加有关。此外，我们已经证明，HSP70的耗尽 在免疫细胞中，TME的另一个重要成分，减少肿瘤的生长和T细胞缺乏 HSP70在体外对胰腺癌细胞的杀伤作用更强。这些数据表明，热休克 TME(免疫与间质)不同成分中的反应/HSP70影响肿瘤生长 雷公藤甲素可能通过调节热休克反应来影响TME。 目前的资助重点是了解热休克反应在生物中的作用。 胰腺癌。在具体目标1中，我们将确认间质HSP70和热休克反应的作用 (HSR)在多种胰腺癌动物模型和人胰腺癌生长中的作用 标本。在目标2中，我们将阐明HSP70和热休克反应在肿瘤中的作用机制。 间质促进肿瘤生长。具体地说，我们将阐明基质HSR的缺乏是否会导致增加 免疫细胞对抗癌细胞的功效。最后，在目标3中，我们将阐明(S) 免疫细胞中的HSP70和HSR促进胰腺癌的生长。具体来说，我们将评估是否 T细胞HSP70/HSR影响T细胞活化和T细胞介导的杀伤。我们认为，对这一问题的澄清 TME中HSP70/HSR调控胰腺癌进展的机制 理解癌细胞用来逃避细胞死亡的机制。

Abstract Several protective mechanisms have evolved to ensure survival of cells under adverse condition. `Heat Shock Response' is one such survival mechanism. We have previously shown that heat shock protein-70, a multi-faceted chaperone protein protects pancreatic acinar cells from damage during acute pancreatitis. We have extended these observations to pancreatic cancer and have demonstrated that (HSP70) is overexpressed in pancreatic cancer cells and plays a very prominent role in protecting cancer cells from cell death. While previous research focused primarily on the properties of the cancer cell, there has recently been increased understanding of the role of the tumor microenvironment (TME) in supporting cancer growth. Pancreatic cancer has an intricate TME, which is believed to contribute to its aggressive behavior. While studies in non-pancreatic tumors suggest that lack of Heat Shock Factor-1 (HSF1) in stroma decreases the growth of, the role of heat shock response pathway in shaping the TME of pancreatic cancer has never been studied. Intriguingly, our data suggest that triptolide, a natural heat shock inhibitor modulates pancreatic cancer TME and depletes stroma. Our preliminary data also suggest that lack of HSP70 in stromal cells is associated with increased cytotoxic T cell infiltration. Furthermore, we have shown that depletion of HSP70 in immune cells, the other important component of TME, decreases growth of tumors and that T cells lacking HSP70 are more effective in killing pancreatic cancer cells in vitro. These data suggest that Heat Shock Response/ HSP70 in various components of TME (immune vs stroma) influence tumor growth and that triptolide could influence TME by modulating heat shock response. The current grant is focused towards understanding the role of Heat shock response in biology of pancreatic cancer. In specific aim 1 we will confirm the role of stromal HSP70 and Heat Shock Response (HSR) in pancreatic cancer growth using a variety of animal models of pancreatic cancer as well as human specimens. In aim 2, we will elucidate the mechanism by which HSP70 and heat shock response in tumor stroma promotes tumor growth. Specifically, we will elucidate if lack of stromal HSR leads to increased efficacy of immune cells against cancer cells. Finally, in aim 3, we will elucidate the mechanism(s) by which HSP70 and HSR in immune cells promote pancreatic cancer growth. Specifically, we will evaluate whether HSP70/HSR in T cells affect T cell activation and T cell mediated killing. We believe that elucidation of the mechanism by which HSP70/HSR in TME modulate pancreatic cancer progression will lead to increased comprehension of the mechanism cancer cell uses to evade cell death.