Functional organization of extracellular hyaluronan, CD44, and RHAMM

Cowman, Mary K.; Turley, Eva A.

doi:10.1002/pgr2.4

Cited by 7 publications

(1 citation statement)

References 279 publications

(583 reference statements)

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“…HA is ubiquitously present in all ECM tissues, showing many important physiological and pathological functions. The best-known role of HA is its structural function; HA acts as a chemical glue, allowing the formation of a stable ECM through the ability to interact with several proteoglycans (such as aggrecan and versican) [27]. Such HA complexes determine tissue mechanical properties, such as flexibility and stiffness.…”

Section: The Role Of Ha In Tumor Stromamentioning

confidence: 99%

Effects of Hyaluronan on Breast Cancer Aggressiveness

Parnigoni

Moretto

Viola

et al. 2023

Cancers

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The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.

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Section: The Role Of Ha In Tumor Stromamentioning

confidence: 99%

Effects of Hyaluronan on Breast Cancer Aggressiveness

Parnigoni

Moretto

Viola

et al. 2023

Cancers

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Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

Mongiat,

Pascal,

Poletto

et al. 2024

Proteoglycan Research

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Antiangiogenic therapy is an established method for the treatment of several cancers and vascular‐related diseases. Most of the agents employed target the vascular endothelial growth factor A, the major cytokine stimulating angiogenesis. However, the efficacy of these treatments is limited by the onset of drug resistance. Therefore, it is of fundamental importance to better understand the mechanisms that regulate angiogenesis and the microenvironmental cues that play significant role and influence patient treatment and outcome. In this context, here we review the importance of the three basement membrane (BM) heparan sulfate proteoglycans (HSPGs), namely perlecan, agrin, and collagen XVIII. These HSPGs are abundantly expressed in the vasculature and, due to their complex molecular architecture, they interact with multiple endothelial cell receptors, deeply affecting their function. Under normal conditions, these proteoglycans exert proangiogenic functions. However, in pathological conditions such as cancer and inflammation, extracellular matrix remodeling leads to the degradation of these large precursor molecules and the liberation of bioactive processed fragments displaying potent angiostatic activity. These unexpected functions have been demonstrated for the C‐terminal fragments of perlecan and collagen XVIII, endorepellin, and endostatin. These bioactive fragments can also induce autophagy in vascular endothelial cells which contributes to angiostasis. Overall, BM proteoglycans deeply affect angiogenesis counterbalancing proangiogenic signals during tumor progression and represent possible means to develop new prognostic biomarkers and novel therapeutic approaches for the treatment of solid tumors.

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The spatial separation of basic amino acids is similar in RHAMM and hyaluronan binding peptide P15‐1 despite different sequences and conformations

Erkanli,

Kang,

Kirsch

et al. 2024

Proteoglycan Research

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Peptides that increase pro‐reparative responses to injury and disease by modulating the functional organization of hyaluronan (HA) with its cell surface binding proteins (e.g., soluble receptor for hyaluronan‐mediated motility [RHAMM] and integral membrane CD44) have potential therapeutic value. The binding of RHAMM to HA is an attractive target, since RHAMM is normally absent or expressed at low levels in homeostatic conditions, but its expression is significantly elevated in the extracellular matrix during tissue stress, response‐to‐injury, and in cancers and inflammation‐based diseases. The HA‐binding site in RHAMM contains two closely spaced sequences of clustered basic amino acids, in an alpha‐helical conformation. In the present communication, we test whether an alpha‐helical conformation is required for effective peptide binding to HA, and competitive disruption of HA–RHAMM interaction. The HA‐binding RHAMM‐competitive peptide P15‐1, identified using the unbiased approach of phage display, was examined using circular dichroism spectroscopy and the conformation‐predictive AI‐based AlphaFold2 algorithm. Unlike the HA‐binding site in RHAMM, peptide P15‐1 was found to adopt irregular conformations in solution rather than alpha helices. Instead, our structural analysis suggests that the primary determinant of peptide‐HA binding is associated with a specific clustering and spacing pattern of basic amino acids, allowing favorable electrostatic interaction with carboxylate groups on HA.

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Functional organization of extracellular hyaluronan, CD44, and RHAMM

Cited by 7 publications

References 279 publications

Effects of Hyaluronan on Breast Cancer Aggressiveness

Effects of Hyaluronan on Breast Cancer Aggressiveness

Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

The spatial separation of basic amino acids is similar in RHAMM and hyaluronan binding peptide P15‐1 despite different sequences and conformations

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