Influence of Hyaluronan Density on the Behavior of Breast Cancer Cells with Different CD44 Expression

Abstract

Molecular gradients are common in biosystems and play an essential role in physiological and pathological processes. During carcinogenesis, for example, hyaluronan (HA) homeostasis is dysregulated by cancer cells and the altered synthesis and degradation processes result in the formation of HA gradients within the tumor microenvironment. Herein, a platform is developed to study the biological role of HA gradient in breast cancer cells. Cells with different aggressiveness and expression of CD44-the main HA receptor usually overexpressed in breast cancers, are selected for this study. The developed platform is compatible with several imaging modalities and allows assessment of cell density, morphology, CD44 expression, and cell motility in a function of HA density. Using high-throughput analysis, it is shown that cells that do not express CD44 do not change along the gradient, while CD44 positive cells respond differently to the HA gradient depending on the level of CD44 expression and HA density. This different response is associated with the activation of different signaling pathways by the CD44-HA interactions. IntroductionCancer development, progression, and recurrence rely on bidirectional communication between cancer cells and the extracellular matrix (ECM). [1] This communication results in ECM remodeling and the formation of both physical and molecular gradients, contributing to a malignant interactome and disease progression. [2] Among different ECM components, hyaluronan (HA)-a linear nonsulfated glycosaminoglycan, is an important player in cancer progression. [1,3] HA synthesis and degradation are tightly regulated, but in most tumors, including breast ones, HA homeostasis is altered, favoring the accumulation of HA fragments and oligosaccharides. [1b,3b,4] The generated fragments modulate the cell behavior of different cell populations within the tumor microenvironment by interaction with

Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery

“…It suggested that OPN and CD44 in protein coronas, as typical proteins related to adhesion and uptake of tumor cells, may promote nanovesicle internalization through OPN-integrin and CD44-mediated ligand-receptor binding 53 . To investigate the role of OPN and CD44 opsonization in cellular uptake, cilengitide (CL) was used to inhibit the interaction between OPN and integrins 54 , 55 , and free hyaluronic acid (HA) was pretreated with tumor cells for competitive binding with CD44 to impede the nanovesicle-CD44 interaction 56 , 57 . The uptake efficiency in both A549 and HeLa cells was reduced after CL or HA preincubation with tumor cells (Fig.…”

Cancer Cell‐Specific Fluorescent Prodrug Delivery Platforms

“…CD44, a glycoprotein on the surface of the cell, participates in immune recognition, cell-to-cell and cell-to-matrix interactions, cell migration, and other processes. [74] HA is a promising ligand for targeting CD44-overexpressing breast cancer cells, such as MDA-MB-231 cells (Figure 5b). However, HA-modified drug carriers accumulate preferentially in the liver after systemic injection, thereby resulting in insufficient accumulation in tumor tissues.…”

Embedded Bioprinting of Breast Tumor Cells and Organoids Using Low‐Concentration Collagen‐Based Bioinks

“…Both collagen I and HA are important ECM components of breast cancer TME. Previous studies in the literature have demonstrated that HA interacts with breast cancer cells via CD44 receptors [34] and the addition of HA can better mimic the biophysical and biochemical microenvironments in breast cancer ECM. [35,36] Therefore, we attempted to prepare a bioink composing both HA and collagen.…”