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The role of inflammation in the development of cancer was described as early as 19th century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new hallmarks of cancer. Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important ECM component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes.

The glycosaminoglycan hyaluronan (HA), a major component of extracellular matrices, and cell surface receptors of HA have been proposed to have pivotal roles in cell proliferation, migration, and invasion, which are necessary for inflammation and cancer progression. CD44 and receptor for HA-mediated motility (RHAMM) are the two main HA-receptors whose biological functions in human and murine inflammations and tumor cells have been investigated comprehensively. HA was initially considered to be only an inert component of connective tissues, but is now known as a \"dynamic\" molecule with a constant turnover in many tissues through rapid metabolism that involves HA molecules of various sizes: high molecular weight HA (HMW HA), low molecular weight HA, and oligosaccharides. The intracellular signaling pathways initiated by HA interactions with CD44 and RHAMM that lead to inflammatory and tumorigenic responses are complex. Interestingly, these molecules have dual functions in inflammations and tumorigenesis. For example, the presence of CD44 is involved in initiation of arthritis, while the absence of CD44 by genetic deletion in an arthritis mouse model increases rather than decreases disease severity. Similar dual functions of CD44 exist in initiation and progression of cancer. RHAMM overexpression is most commonly linked to cancer progression, whereas loss of RHAMM is associated with malignant peripheral nerve sheath tumor growth. HA may similarly perform dual functions. An abundance of HMW HA can promote malignant cell proliferation and development of cancer, whereas antagonists to HA-CD44 signaling inhibit tumor cell growth in vitro and in vivo by interfering with HMW HA-CD44 interaction. This review describes the roles of HA interactions with CD44 and RHAMM in inflammatory responses and tumor development/progression, and how therapeutic strategies that block these key inflammatory/tumorigenic processes may be developed in rodent and human diseases.

Skin aging is a multifactorial process consisting of two distinct and independent mechanisms: intrinsic and extrinsic aging. Youthful skin retains its turgor, resilience and pliability, among others, due to its high content of water. Daily external injury, in addition to the normal process of aging, causes loss of moisture. The key molecule involved in skin moisture is hyaluronic acid (HA) that has unique capacity in retaining water. There are multiple sites for the control of HA synthesis, deposition, cell and protein association and degradation, reflecting the complexity of HA metabolism. The enzymes that synthesize or catabolize HA and HA receptors responsible for many of the functions of HA are all multigene families with distinct patterns of tissue expression. Understanding the metabolism of HA in the different layers of the skin and the interactions of HA with other skin components will facilitate the ability to modulate skin moisture in a rational manner.

Hyaluronan (HA) is a glycosaminoglycan with a simple structure but diverse and often opposing functions. The biological activities of this polysaccharide depend on its molecular weight and the identity of interacting receptors. HA is initially synthesized as high molecular-weight (HMW) polymers, which maintain homeostasis and restrain cell proliferation and migration in normal tissues. These HMW-HA functions are mediated by constitutively expressed receptors including CD44, LYVE-1, and STABILIN2. During normal processes such as tissue remodeling and wound healing, HMW-HA is fragmented into low molecular weight polymers (LMW-HA) by hyaluronidases and free radicals, which promote inflammation, immune cell recruitment and the epithelial cell migration. These functions are mediated by RHAMM and TLR2,4, which coordinate signaling with CD44 and other HA receptors. Tumor cells hijack the normally tightly regulated HA production/fragmentation associated with wound repair/remodeling, and these HA functions participate in driving and maintaining malignant progression. However, elevated HMW-HA production in the absence of fragmentation is linked to cancer resistance. The controlled production of HA polymer sizes and their functions are predicted to be key to dissecting the role of microenvironment in permitting or restraining the oncogenic potential of tissues. This review focuses on the dual nature of HA in cancer initiation vs. resistance, and the therapeutic potential of HA for chemo-prevention and as a target for cancer management.

The functional complexity of higher organisms is not easily accounted for by the size of their genomes. Rather, complexity appears to be generated by transcriptional, translational, and post-translational mechanisms and tissue organization that produces a context-dependent response of cells to specific stimuli. One property of gene products that likely increases the ability of cells to respond to stimuli with complexity is the multifunctionality of expressed proteins. Receptor for hyaluronan-mediated motility (RHAMM) is an example of a multifunctional protein that controls differential responses of cells in response-to-injury contexts. Here, we trace its evolution into a sensor-transducer of tissue injury signals in higher organisms through the detection of hyaluronan (HA) that accumulates in injured microenvironments. Our goal is to highlight the domain and isoform structures that generate RHAMM’s function complexity and model approaches for targeting its key functions to control cancer progression.

The cancer stem cell (CSC) theory features typically rare self‐renewing subpopulations that reconstitute the heterogeneous tumor. Identification of molecules that characterize the features of CSCs is a key imperative for further understanding tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids that are miniature forms of tumor tissues by reconstructing cellular diversity to identify specific markers to characterize CSCs in heterogeneous tumors. Here, we report that the receptor for hyaluronan‐mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single‐cell transcriptomics of organoids highlighted RHAMM‐positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+CD44+ cells from the human colorectal cancer tissues showed highly proliferative characteristics with a self‐renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoid formation in vitro and inhibited tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction. This research highlights RHAMM+ proliferative cells within the conventional CD44+ colorectal cancer stem cell fraction. The identification of cycling cells within cancer stem cells led to a better characterization of tumor heterogeneity and the potential development of a novel therapeutic strategy.

Background RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM +ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. Methods We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm −/− mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm -loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. Results Rhamm -loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm -loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm −/− primary tumor clones that are enriched in lung metastases. Rhamm −/− tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM +ve tumor cells to a significantly greater extent than RHAMM −ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. Conclusion RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Background Non-small cell lung cancers (NSCLC) account for most cases of lung cancer. More effort is needed to research new drug and combination therapies for this disease. An anthraquinone derivative, emodin shows anticancer potency. We hypothesis that emodin suppresses lung cancer cells through hyaluronan (HA) synthase 2-HA-CD44/receptor for hyaluronic acid-mediated motility (RHAMM) interaction-dependent signaling pathway mediated cell cycle regulation. Methods We tested the effect of emodin on viability, apoptosis, and HA secretion of 5 NSCLC cell lines. We used NSCLC cells A549 for two rounds of knockdown study: (1) knocking down either the synthases (HAS2 and HAS3) or the receptors (CD44 and RHAMM); (2) knocking down either HAS2 or HAS3. Then determined the effect of emodin on viability, HA secretion, cell cycle, and expression of cyclin proteins. Results Emodin suppressed viability and HA secretion of all 5 NSCLC cell lines except for HA secretion of H460. Emodin had a slight apoptosis induction effect on all cell lines and was not different among cell lines. The knockdown of either the synthases or the receptors blocked emodin effects on viability while the knockdown of HAS2 block emodin effects but not HAS3. Emodin increased cells in the G1/G0 phase, and decreased cells in the S and G2/M phase by down-regulating cyclin A and B and up-regulating cyclin C, D, and E. HAS2 knockdown blocked the effects of emodin on the cell cycle. Conclusions This study demonstrated that emodin regulates the cell cycle of NSCLC cells through the HAS2-HA-CD44/RHAMM interaction-dependent signaling pathway.

The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.