Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer progression. Due to the reliance of cancer cells on Hsp90’s chaperone function to sustain tumor growth and spread, Hsp90 inhibitors have been the subject of numerous clinical trials over the past two decades. However, these efforts have largely been unsuccessful, primarily due to the cellular toxicity caused by pan-Hsp90 inhibitors at doses required for anticancer efficacy. Therefore, novel approaches to target Hsp90 are necessary. An identified subpopulation of Hsp90 located outside cells (eHsp90) may offer a promising alternative as a therapeutic target against cancer. Studies including our own have shown that eHsp90 is released specifically by cancer cells, and eHsp90 has unique interactors and functions extracellularly to promote tumor invasiveness, the initial step in metastasis. Inhibition of eHsp90 has been shown to suppress metastasis in animal models, indicating its therapeutic potential, although the underlying mechanisms remain incompletely understood. Cancer cells modulate the tumor microenvironment (TME) during the invasion, especially the ECM proteins and the state of the ECM is a strong predictor of invasive and metastatic cancer. Given that most of the known eHsp90 clients are ECM proteins or are proteins involved in ECM modulation, ECM remodelling could be the key mechanism through which eHsp90 enhances invasiveness. This review will focus on ECM modulation by eHsp90 as a driver of cancer invasion and metastasis. We will also discuss the potency of inhibiting eHsp90 in inhibiting invasion and metastatic spread in preclinical models and the using circulating Hsp90 patient samples as a biomarker of cancer invasion and metastasis.
在寻找有效癌症疗法的过程中，识别参与肿瘤侵袭和转移的蛋白质仍是一个关键且尚未满足的需求。Hsp90作为一种丰富的细胞内分子伴侣蛋白，在维持细胞稳态中发挥关键作用，其活性升高对癌症进展至关重要。由于癌细胞依赖Hsp90的分子伴侣功能来维持肿瘤生长和扩散，过去二十年间Hsp90抑制剂已成为众多临床试验的研究对象。然而，这些努力大多未能成功，主要原因是泛Hsp90抑制剂在达到抗癌疗效所需剂量时会引起细胞毒性。因此，需要开发靶向Hsp90的新方法。已发现的位于细胞外的Hsp90亚群（eHsp90）可能为癌症治疗靶点提供一个有前景的替代选择。包括我们在内的研究表明，eHsp90由癌细胞特异性释放，并在细胞外通过独特的相互作用因子和功能促进肿瘤侵袭——这是转移过程的第一步。抑制eHsp90已被证明能在动物模型中抑制转移，表明其治疗潜力，尽管其潜在机制尚未完全阐明。癌细胞在侵袭过程中会调节肿瘤微环境（TME），尤其是细胞外基质（ECM）蛋白，而ECM的状态是预测侵袭性和转移性癌症的重要指标。鉴于大多数已知的eHsp90底物是ECM蛋白或参与ECM调节的蛋白，ECM重塑可能是eHsp90增强侵袭性的关键机制。本综述将重点关注eHsp90通过调节ECM驱动癌症侵袭和转移的作用。我们还将讨论在临床前模型中抑制eHsp90对抑制侵袭和转移扩散的效力，以及将循环Hsp90患者样本作为癌症侵袭和转移生物标志物的应用前景。
The Role of eHsp90 in Extracellular Matrix Remodeling, Tumor Invasiveness, and Metastasis
肿瘤(癌症)患者之家