Hyaluronan in Cancer Biology

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Pancreatic ductal adenocarcinoma PDAC remains the most deadly disease worldwide, with the lowest survival rate among all cancer types. Recent evidence suggests that hyaluronan HA , a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma is typically characterized by a dense desmoplastic stroma containing a large amount of HA.

In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA. Pancreatic ductal adenocarcinoma PDAC is one of the most aggressive and intractable solid tumors, which often invades surrounding stromal components, including lymphatic, vascular, and perineural systems, ultimately metastasizing to distant organs. Despite recent advances in the clinical management, the survival rate in patients with PDAC remains the lowest among all cancer types, emphasizing the need for a better understanding of its biology.

The biology and role of CD44 in cancer progression: therapeutic implications

In particular, identification of molecular mechanisms underlying the aggressive behaviors of PDAC can provide the basis for the development of novel therapeutic intervention. The progression of cancer is governed by complex mechanisms and is significantly accelerated by the tumor microenvironment, composed of a variety of stromal cells and ECM. In normal physiological conditions, the amount of HA is controlled by a balance between synthesis and degradation; however, HA has been shown to be abundantly accumulated in the surrounding stroma of malignant tumor.

In this review article, we summarize the current understanding of the role of HA in PDAC and discuss its potential therapeutic applications. Newly synthesized HA molecules are extruded directly onto the cell surface for assembly into pericellular or extracellular matrices. Importantly, variants of CD44, specifically CD44v6, have been shown to promote tumor progression and metastatic spread in lung, breast, and colon cancer. Hyaluronin is distributed ubiquitously throughout human tissue and plays an important role in structuring tissue architecture based on its characteristic hydrodynamic properties.

However, HA is also involved in various inflammatory and pathological conditions. In many types of malignant tumors, HA is often overexpressed or highly concentrated in tumor cells and, particularly, in their surrounding ECM. For example, HA expression in tumor cells is associated with poor survival in patients with gastric and colorectal cancers.

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In addition to these clinical findings, there is considerable experimental evidence supporting the role of HA in cancer initiation and progression. For example, overexpression of Has2 in mammary glands resulted in the development of mammary tumors in a transgenic mouse model. In terms of cancer progression, suppression of HA production by antisense inhibition of HAS blocked growth of prostate cancer 36 and invasion of colon cancer cells.

A close link between HA and epithelial—mesenchymal transition also supports the role of HA in cancer initiation and progression. Interestingly, the size of HA is important in terms of its effects on cancer initiation, growth, and progression, although the actions of different sizes of HA are diverse and complex. For example, a previous study showed that HA is secreted from cultured human pancreatic cancer cell lines. A comprehensive analysis of the HA content in a variety of human malignant tumors revealed that PDAC had the highest incidence of detectable HA content, which was predominantly associated with the desmoplastic stroma rather than with tumor cells.

Furthermore, strong expression of HAS2 and weak expression of HYAL1 were significantly associated with shorter survival time after surgery. Previous studies using immunohistochemistry have shown that CD44 is highly expressed on the membrane mainly on the basolateral membrane of PDAC cells. Teranishi et al. Circulating tumor cell CTC clusters were originally described in the 's and are now considered to be pre-cursors of metastatic colonies.

In mouse breast cancer models, circulating tumor cell clusters exhibit higher metastatic capacity compared with individual or single CTCs Aceto et al.

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Quantification of these CTC clusters in breast cancer patients show that their presence correlates with reduced progression-free survival and poor outcome Cheung et al. Collective migration of tumor cell clusters into the circulation appears to offer a tumor cell survival advantage compared to entry of single tumor cells into the vasculature. Mouse metastasis models suggest that circulating CAFs can exit either with groups of cancer cells or by themselves. Additionally, since CAFs are present in pre-metastatic niches prior to the appearance of tumor cells, circulating CAFs likely also play a role in establishing or preparing a niche suitable for future tumor cell colonization.

In a pilot study, cCAFs were detected in the blood from patient with Stage IV metastatic breast cancer but not from patients with Stage I disease with no evidence of relapse, while CTCs were detected in both patient samples Ao et al. The development of techniques for isolating circulating CAFs from mouse models of human breast cancer xenografts and mammary tumor susceptibility will greatly aid in characterizing both the origin and contribution of circulating CAFs to successful metastasis.

Recent evidence suggests that at least a portion of CTCs are tumor cells transitioning between the epithelial and mesenchymal state Yu et al. Figure 4. From Ao et al.


A CAF property that appears to be critical to cancer cell invasion is their active motility and tropism toward tumor cells e. These properties culminate in close physical heterotypic contact Marusyk et al. Clinically, close proximity of CAFs to tumor cells is linked to poor outcome and resistance to therapy and supports migration and invasion of tumor cells by several mechanisms Marusyk et al. We and others e. Such tumor cells are able to invade independently from CAFs Turley et al. Intriguingly, we have shown using fluorescent HA-probes that HA-binding to breast cancer cells and to activated fibroblasts is heterogeneous Veiseh et al.

FACS-sorted tumor cell subsets that bind high levels of HA are more motile, invasive and metastatic than subsets that bind low or no probe. A concept that emerges from these studies is that CAF subsets not only utilize HA to migrate close to tumor cells but that their autocrine production of HA also stimulates the migration of the HA binding tumor subpopulation Figure 5.

Figure 5.

Cancer Biology, page 12 | eLife

Hyaluronan promotes CAFs motility toward tumor cells and tumor cell motility. CAF subsets produce hyaluronan as a motogenic stimulus for migrating toward tumor cells. However, several studies have reported that circulating tumor cells from cancer patients express the HA receptor CD44 Grillet et al. While these advances are encouraging, they are currently either effective in a minority of cancer patients, have significant pro-tumor side-effects or lack long-term durability.

Thus, new approaches are necessary to expand the number of patients who will benefit clinically from chemotherapy and targeted therapy. Targeting the fibrotic stroma is emerging as a potentially key approach necessary to achieving therapeutic efficacy. Therapies that target the fibrotic stroma, including HA, are being developed and entering clinical trials Provenzano and Hingorani, ; Jiang et al. High interstitial pressures in the fibrotic stroma of pancreatic cancers, which results from high production of collagen and HA, causes the collapse of the stromal vasculature in pancreatic cancers and impedes exposure of tumor cells to chemo- and immune therapies Yu and Tannock, Multiple approaches to target fibrotic stroma are therefore being tested to overcome these delivery issues.

One successful strategy is targeting HA. Systemic administration of a recombinant sperm hyaluronidase PEGPH20 , degrades hyaluronan in pancreatic cancer stroma Provenzano and Hingorani, This destruction decreases interstitial fluid pressure, increases vasculature patency and improves the delivery of gemcitabine.

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  5. Importantly, these hyaluronidase-mediated changes both decrease tumor volume and increase animal survival in experimental models of pancreatic cancer. An alternative to the use of recombinant hyaluronidase has been of HA synthesis inhibitors e. CAF-targeted therapies are also being developed to blunt their fibrosis-activated signaling.

    This inhibitor reduces fibrosis, decreases the number of tumor-infiltrating immuno-suppressive cells and results in survival doubling in mouse models of pancreatic ductal adenocarcinoma Jiang et al. Inhibiting FAK activation also increases responsiveness to chemotherapy and immune checkpoint inhibitors with resulting improved outcome. These pre-clinical successes have led to phase 1 clinical trials using this FAK inhibitor in combination with immune checkpoint inhibitors Jiang et al.

    Off target effects of VS could contribute to immune-suppression and therefore compromise its effective utility in humans Jiang et al. Active investigations are also underway to target CAF survival in the fibrotic stroma. In contrast to carcinoma cells, CAFs are genetically normal cells that have been co-opted and modified by cancer cells into a state of constitutive activation. CAFs therefore have a less plastic genome than tumor cells limiting their ability to rapidly modify their genome but making them an attractive candidate for stable responses to targeted therapy.

    In vivo administration of a FAP enzyme inhibitor, Talabostat, in tumor-bearing mice results in tumor regression and upregulation of specific chemokines and cytokines that induce an anti-tumor immune response Cunningham, Talabostat is well tolerated in healthy volunteers in both Phase I and II clinical trials but does not result in therapeutic benefit. FAP-targeted chimeric antigen receptor CAR T cells reduce ECM, vessel density, and growth of several types of human cancer xenografts and murine pancreatic cancers when introduced into mice by adoptive transfer Wang et al.

    This technology has not yet entered clinical trials. In conclusion, despite recent advances in targeted therapies, metastases, recurrence and relapse remain as major clinical obstacles to successful cancer treatment. Carcinoma cell epigenetic and genetic heterogeneity are important factors that limit therapeutic efficacy. However, a wealth of studies has now demonstrated that tumor-associated fibrotic stroma is also a major contributing factor to therapeutic failure.