Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression.

Sonic hedgehog (SHH) signaling is an important promotor of desmoplasia, a critical feature in pancreatic cancer stromal reactions involving the activation of pancreatic stellate cells (PSCs). Gremlin 1 is widely overexpressed in cancer-associated stromal cells, including activated PSCs. In embryonic development, SHH is a potent regulator of Gremlin 1 through an interaction network. This subtle mechanism in the cancer microenvironment remains to be fully elucidated. The present study investigated the association between Gremlin 1 and SHH, and the effect of Gremlin 1 in pancreatic cancer. The expression of Gremlin 1 in different specimens was measured using immunohistochemistry. The correlations among clinicopathological features and levels of Gremlin 1 were evaluated. Primary human PSCs and pancreatic cancer cell lines were exposed to SHH, cyclopamine, GLI family zinc finger-1 (Gli-1) small interfering RNA (siRNA), and Gremlin 1 siRNA to examine their associations and effects using an MTT assay, reverse transcription-quantitative polymerase chain reaction analysis, western blot analysis, and migration or invasion assays. The results revealed the overexpression of Gremlin 1 in pancreatic cancer tissues, mainly in the stroma. The levels of Gremlin 1 were significantly correlated with survival rate and pT status. In addition, following activation of the PSCs, the expression levels of Gremlin 1 increased substantially. SHH acts as a potent promoter of the expression of Gremlin 1, and cyclopamine and Gli-1 siRNA modulated this effect. In a screen of pancreatic cancer cell lines, AsPC-1 and BxPC-3 cells expressed high levels of Gremlin 1, but only AsPC-1 cells exhibited a high expression level of SHH. The results of the indirect co-culture experiment suggested that paracrine SHH from the AsPC-1 cells induced the expression of Gremlin 1 in the PSCs. Furthermore, Gremlin 1 siRNA negatively regulated the proliferation and migration of PSCs, and the proliferation, invasion and epithelial-mesenchymal transition of AsPC-1 and BxPC-3 cells. Based on the data from the present study, it was concluded that an abnormal expression level of Gremlin 1 in pancreatic cancer was induced by SHH signaling, and that the overexpression of Gremlin 1 enabled pancreatic cancer progression.

Heparanase expression in blood is sensitive to monitor response to anticancer treatment in pancreatic cancer, a pilot study.

BACKGROUND: /Objectives: High heparanase level was shown in maliganant tumor; however, whether or not heparanase may serve as a sensitive marker to monitor response to anticancer treatment is still unknown. METHODS: In the pilot study, heparanase mRNA expression in peripheral blood mononuclear cell fraction (PBMC) and activity in plasma and urine were detected by quantitative real time RT-PCR and heparan-degrading enzyme assay in 31 pancreatic cancer patients. RESULTS: Heparanase mRNA and activity in samples from cancer patients were significantly higher than that in healthy donors. Both heparanase mRNA and activity in plasma and urine decreased significantly in 17 patients who underwent R0 resection, but increased remarkably in 6 patients when recurrence or metastasis occurred (P < 0.05). However, those who underwent R1 or R2 resection in 6 patients kept stable. For 8 patients who received chemotherapy, heparanase mRNA and activity in plasma and urine decreased in each of the samples (P < 0.05). Patients with high heparanase mRNA (≥a cutoff value of 1.84) in PBMC and activity in plasma (≥1.30U/ml) were associated with a poor postoperative survival (P = 0.02 and P = 0.04). CONCLUSIONS: Heparanase mRNA in PBMC and activity in plasma are closely correlated with therapeutic responsiveness and survival time, indicating that heparanase level in blood might be a sensitive but non-specific marker to monitor patients' response to anticancer treatment and to predict survival.

Hyperglycemia, a neglected factor during cancer progression.

Recent evidence from large cohort studies suggests that there exists a higher cancer incidence in people with type 2 diabetes (DM2). However, to date, the potential reasons for this association remain unclear. Hyperglycemia, the most important feature of diabetes, may be responsible for the excess glucose supply for these glucose-hungry cells, and it contributes to apoptosis resistance, oncogenesis, and tumor cell resistance to chemotherapy. Considering associations between diabetes and malignancies, the effect of hyperglycemia on cancer progression in cancer patients with abnormal blood glucose should not be neglected. In this paper, we describe the role that hyperglycemia plays in cancer progression and treatment and illustrate that hyperglycemia may contribute to a more malignant phenotype of cancer cells and lead to drug resistance. Therefore, controlling hyperglycemia may have important therapeutic implications in cancer patients.