The development of delivery systems capable of tumor targeting represents a promising strategy to overcome issues related to nonspecific effects of conventional anticancer therapies. Currently, one of the most investigated agents for cancer targeting is hyaluronic acid (HA), since its receptor, CD44, is overexpressed in many cancers. However, most of the studies on CD44/HA interaction have been so far performed in cell-free or genetically modified systems, thus leaving some uncertainty regarding which cell-related factors influence HA binding and internalization (collectively called "uptake") into CD44-expressing cells. To address this, the expression of CD44 (both standard and variants, designated CD44s and CD44v, respectively) was evaluated in human dermal fibroblasts (HDFs) and a large panel of cancer cell lines, including breast, prostate, head and neck, pancreatic, ovarian, colorectal, thyroid, and endometrial cancers. Results showed that CD44 isoform profiles and expression levels vary across the cancer cell lines and HDF and are not consistent within the cell origin. Using composite information of CD44 expression, HA binding, and internalization, we found that the expression of CD44v can negatively influence the uptake of HA, and, instead, when cells primarily expressed CD44s, a positive correlation was observed between expression and uptake. In other words, CD44shigh cells bound and internalized more HA compared to CD44slow cells. Moreover, CD44shigh HDFs were less efficient in uptaking HA compared to CD44shigh cancer cells. The experiments described here are the first step toward understanding the interplay between CD44 expression, its functionality, and the underlying mechanism(s) for HA uptake. The results show that factors other than the amount of CD44 receptor can play a role in the interaction with HA, and this represents an important advance with respect to the design of HA-based carriers and the selection of tumors to treat according to their CD44 expression profile.

中文翻译：

---

评估透明质酸通过CD44靶向肿瘤的效率。

能够靶向肿瘤的递送系统的发展代表了一种有前途的策略，可以克服与常规抗癌疗法的非特异性作用有关的问题。目前，最受研究的癌症靶向药物之一是透明质酸（HA），因为其受体CD44在许多癌症中均过表达。但是，到目前为止，大多数关于CD44 / HA相互作用的研究都是在无细胞或基因改造的系统中进行的，因此对于哪些细胞相关因素会影响HA与CD44-的结合和内在化（统称为“摄取”）还存在一些不确定性。表达细胞。为了解决这个问题，我们评估了人类皮肤成纤维细胞（HDF）和一大堆癌细胞系（包括乳腺癌）中CD44（分别为标准品和变体，分别命名为CD44s和CD44v）的表达，前列腺癌，头颈癌，胰腺癌，卵巢癌，大肠癌，甲状腺癌和子宫内膜癌。结果显示，CD44同工型谱和表达水平在癌细胞系和HDF之间有所不同，并且在细胞起源内不一致。使用CD44表达，HA结合和内在化的复合信息，我们发现CD44v的表达可以负面影响HA的摄取，相反，当细胞主要表达CD44s时，表达与摄取之间存在正相关。换句话说，与CD44slow细胞相比，CD44shigh细胞结合并内化了更多的HA。此外，与CD44高癌细胞相比，CD44高HDF在摄取HA方面效率较低。这里介绍的实验是了解CD44表达，其功能，以及高铁摄入的潜在机制。结果表明，除了CD44受体的数量外，其他因素也可能与HA相互作用，这在基于HA的载体设计以及根据CD44表达的治疗方法选择方面代表了重要的进展。轮廓。