Cell–cell contact control of proliferation and migration (also know as contact inhibition) are fundamental protectors of tissue architecture and homeostasis:^[1^] Their loss, and consequently tissue architecture loss, are key factors in cancer initiation.^[2^] A complex and context‐dependent interaction between p53 and HIPPO signaling pathways maintains this tissue architectural homeostasis,^[3^] which is synchronized by cell–cell contact, cell polarity and cell‐extracellular matrix interactions.^[4^] The polysaccharide hyaluronan is emerging as a central extracellular matrix factor connecting these two pathways to tumor resistance or susceptibility.

Hyaluronan is a simple molecule that encodes functional complexity in its size: its native form generally opposes the signaling activity of fragmented polymers:^[5^] Native hyaluronan suppresses inflammation, while fragments promote inflammation.^[6^] The elevated production and fragmentation of hyaluronan is linked to the progression of many tumors.^[7^] However, study of the tumor‐resistant naked mole rat reveals native hyaluronan as essential for controlling cell–cell contact inhibition of growth and tumor resistance.^[8^]

Ooki and Hatakeyama and co‐workers originally showed that native hyaluronan is a HIPPO pathway ligand,^[9^] and their timely review in this issue of BioEssays highlights their own and other studies linking hyaluronan receptors (CD44 and RHAMM/HMMR) to HIPPO regulation. The authors succinctly summarize the complex HIPPO signaling pathway and clearly detail the size‐dependent functions of the hyaluronan polymer that contribute to cancer initiation versus suppression, particularly as they relate to HIPPO signaling. This focus is novel, both in the fields of hyaluronan biology and more broadly tumor biology. However, some readers will feel that the authors should have included a discussion of the intricate connections between the HIPPO and p53 pathways, particularly those mediated by hyaluronan. For example, Tian et al.^[10^] recently showed a critical role of hyaluronan in p53 signaling contact inhibition, while others have demonstrated that expression of CD44 and RHAMM, which mediate effects of hyaluronan,^[5^] are both subject to p53 regulation^[11^] and participate in the HIPPO signaling pathway.^[12^]

Hyaluronan is a neglected factor in the tissue architecture, cell polarity, and contact inhibition literature. This review should stimulate interest in critically assessing its role in maintaining tissue homeostasis.

细胞与细胞之间的增殖和迁移接触控制（也称为接触抑制）是组织结构和体内平衡的基本保护者：^[ 1 ^]它们的丧失以及随之而来的组织结构的丧失是引发癌症的关键因素。^[ 2 ^] p53和HIPPO信号通路之间复杂且依赖于上下文的相互作用维持了这种组织结构的稳态，^[ 3 ^]通过细胞与细胞之间的接触，细胞极性和细胞与细胞外基质的相互作用而同步。^[ 4 ^] 透明质酸多糖正逐渐成为一种重要的细胞外基质因子，将这两种途径与肿瘤的耐药性或易感性联系起来。

透明质酸是一个简单的分子，其大小编码功能复杂性：其天然形式通常与片段化聚合物的信号传导活性相反：^[ 5 ^]天然透明质酸抑制炎症，而片段促进炎症。^[ 6 ^]透明质酸的生产增加和断裂与许多肿瘤的进展有关。^[ 7 ^]但是，对抗肿瘤裸鼠的研究表明，天然透明质酸对于控制细胞与细胞接触的生长抑制和抗肿瘤作用至关重要。^[ 8 ^]

Ooki和Hatakeyama及其同事最初表明，天然的乙酰透明质酸是HIPPO途径的配体，^[ 9 ^]并且他们在本期《BioEssays》上的及时评论着重介绍了他们自己的研究以及将透明质酸受体（CD44和RHAMM / HMMR）与HIPPO调节联系起来的其他研究。作者简要总结了复杂的HIPPO信号传导途径，并明确详述了透明质酸聚合物的大小依赖性功能，这些功能与癌症的发生和抑制有关，尤其是与HIPPO信号传导有关。无论是在透明质酸生物学领域还是在更广泛的肿瘤生物学领域，这种关注都是新颖的。但是，有些读者会认为作者应该对HIPPO和p53途径之间的复杂联系进行讨论，尤其是由透明质酸介导的途径。例如，Tian等。^[ 10 ^]最近显示透明质酸在p53信号接触抑制中起关键作用，而其他人已证明介导透明质酸作用的CD44和RHAMM的表达^[ 5 ^]均受p53调控^[ 11 ^]并参与HIPPO信号通路。^[ 12 ^]

透明质酸是组织结构，细胞极性和接触抑制文献中被忽略的因素。这篇综述应该激发人们对严格评估其在维持组织稳态中的作用的兴趣。