Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.

Investigating the molecular control of deer antler extract on articular cartilage.

BACKGROUND: Deer antler is considered as a precious traditional Chinese medicinal material and has been widely used to reinforce kidney's yang, nourish essence, and strengthen bone function. The most prominent bioactive components in deer antler are water-soluble proteins that play potential roles in bone formation and repair. The aim of this study was to explore the molecular control and therapeutic targets of deer antler extract (DAE) on articular cartilage. METHODS: DAE was prepared as previously described. All rats were randomly divided into Blank group and DAE group (10 rats per group) after 7-day adaptive feeding. The rats in DAE group were orally administrated with DAE at a dose of 0.2 g/kg per day for 3 weeks, and the rats in Blank group were fed with drinking water. Total RNA was isolated from the articular cartilage of knee joints. RNA sequencing (RNA-seq) experiment combined with quantitative real-time polymerase chain reaction (qRT-PCR) verification assay was carried out to explore the molecular control and therapeutic targets of DAE on articular cartilage. RESULTS: We demonstrated that DAE significantly increased the expression levels of functional genes involved in cartilage formation, growth, and repair and decreased the expression levels of susceptibility genes involved in the pathophysiology of osteoarthritis. CONCLUSIONS: DAE might serve as a candidate supplement for maintaining cartilage homeostasis and preventing cartilage degeneration and inflammation. These effects were possibly achieved by accelerating the expression of functional genes involved in chondrocyte commitment, survival, proliferation, and differentiation and suppressing the expression of susceptibility genes involved in the pathophysiology of osteoarthritis. Thus, our findings will contribute towards deepening the knowledge about the molecular control and therapeutic targets of DAE on the treatment of cartilage-related diseases.

Hyaluronan oligosaccharide-induced activation of transcription factors in bovine articular chondrocytes.

OBJECTIVE: To document the activity profile of transcription factors following chondrocyte stimulation with hyaluronan (HA) hexasaccharides (HA(6)) and to determine the expression of genes whose transcriptional activation is tightly associated with the transcription factors. METHODS: Nuclear extracts from bovine articular chondrocytes treated with HA(6) were subjected to transcription factor protein-DNA array analysis. Electrophoretic mobility shift assay (EMSA) analyses were performed to confirm the results of protein-DNA array. The gene expressions of matrix metalloproteinase 3 (MMP-3), type II collagen, and cartilage oligomeric matrix protein (COMP) were examined by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), and protease activity was assessed by casein zymography. RESULTS: In the protein-DNA array analysis, 12 transcription factors were up-regulated and 2 transcription factors were down-regulated in the chondrocytes treated with HA(6). The transcription factors retinoic acid receptor (RAR), retinoid X receptor (RXR), and Sp-1 exhibited >2-fold increased activity by HA(6) treatment, as confirmed by EMSA. RT-PCR analysis showed that the expression levels of MMP-3, type II collagen, and COMP messenger RNA, which are tightly associated with the activation of RAR, RXR, or Sp-1, were up-regulated by treatment with HA(6). Addition of high molecular mass HA after HA(6) treatment resulted in abrogation of the MMP-3 induction. CONCLUSION: These results suggest that HA(6) increase the activity of multiple transcription factors in chondrocytes and signal the enhanced expression of key genes involved in cartilage-matrix remodeling and turnover. The data also demonstrate that high molecular mass HA has a potential to suppress the signaling activated by HA(6).