The purpose of this study is to clarify the contribution of the Hedgehog signaling pathway (Hh pathway) to the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). A total of 149 surgically resected mammary disease specimens and 12 sentinel lymph nodes with micro-metastasis (Ly-met) were studied. The degree of Hh pathway activation was estimated from the Gli1 nuclear staining ratio (%Gli1 nuclear translocation) in cancer cells. The invasiveness of breast cancer cells was determined using Matrigel assays. A serial increase of %Gli1 nuclear translocation to IDC from non-neoplastic diseases was confirmed. In tumor specimens, %Gli1 nuclear translocation correlated with the invasiveness of each type of mammary disease and also correlated with invasion-related histopathological parameters. The %Gli1 nuclear translocation in lymph nodes with micro-metastasis was similar to that in primary sites and higher than that in DCIS with microinvasion and DCIS. Blockade of the Hh pathway decreased the invasiveness of breast cancer cells. In IDC, %Gli1 nuclear translocation correlated with the expression of estrogen receptor-a. Estrogen increased %Gli1 nuclear translocation and the invasiveness of estrogen receptor-a-positive cells. The Hh pathway mediates progression from a non-invasive phenotype to an invasive phenotype and %Gli1 nuclear translocation may be useful as a predictive marker for evaluating the ability of invasiveness. (Cancer Sci 2011; 102: 373-381) B reast cancer is the most common neoplasm among women worldwide. Although the development of new therapies has prolonged the survival time of breast cancer patients year on year,(1,2) we must understand more deeply the biological and molecular mechanisms underlying the progression of breast cancer in order to develop more suitable therapeutic strategies. Thus, we focused on the investigation of functional molecules that mediate the progression from non-invasive to invasive breast cancer. Ductal carcinoma in situ is generally considered to be a precursor of IDC. However, the molecular mechanisms underlying the progression from DCIS to IDC are still unclear.The Hh pathway plays a crucial role in growth and patterning during embryonic development.(3) In adults, the Hh pathway remains active in selected cells. (4,5) In mammary glands, the Hh pathway is strictly controlled to ensure normal mammary gland development and to avoid carcinogenesis.(6-9) The Hh pathway consists of Hh proteins (Shh, Indian Hh, and Desert Hh), 12 transmembrane Patched proteins (Patched 1 and Patched 2), the seven transmembrane protein, Smo, and the five-zinc finger transcription factors Gli2 and Gli3. (3,(10)(11)(12) In the absence of Hh, Patched suppresses the signaling activity of Smo. Hh binds to Patched, and Smo is no longer suppressed. Activated Smo allows the translocation of Glis to the nucleus, where it activates Hh target genes. Gli1 is one of these target genes and is itself a transcriptional factor for the Hh pathway.(3,13-15) Thus, Gli1 expression, esp...
BACKGROUND: Oestrogen receptor-alpha (ERa) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERa-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. METHODS: We used 17-b-oestradiol (E2) as a stimulator against the ERa pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERa (ERa siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERa-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. RESULTS: In ERa-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-b-Oestradiol-induced cell proliferation was suppressed by ICI, ERa siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERa siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERa and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERa and Hh pathways. CONCLUSION: Our data indicate that activation of the ERa pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERa-positive gastric cancer.
Recently, it was reported that Hh signaling is activated in tumor stromal cells but not in tumor cells themselves and that stromal cells may play a role in the proliferation of cancer cells. This suggests the possibility that stromal cells have an important role in the proliferation of tumor cells that may be mediated through Hh signaling. In this report, we present for the first time that inflammation-stimulated monocytes produce Shh through activation of the NF-kappaB signaling pathway, and that the Shh produced promotes the proliferation of pancreatic cancer cells in a paracrine manner through Hh signaling.
The study findings suggest that, under the guidance of trainer surgeons, trainee surgeons with little experience with open gastrectomy and even without prior experience with LDG can perform radical surgeries safely.
The purpose of this study was to evaluate the clinicopathological features and prognosis of patients who underwent surgery for remnant gastric cancer (RGC) during/after the regular five-year follow-up period after initial distal gastrectomy for gastric cancer that is recommended by the Japanese gastric cancer treatment guidelines. Between January 2007 and December 2017, 40 patients underwent surgery for RGC after distal gastrectomy. Twenty-eight of the 40 patients underwent initial gastrectomy for cancer. We divided the 28 patients into two groups: patients who were diagnosed with RGC during/after the five-year follow-up period after initial gastrectomy, and analyzed their retrospectively collected data. Among the 28 patients, 15 patients were diagnosed with RGC within five years and 13 patients were diagnosed with RGC after five years. There were significant differences in the reconstruction of the initial operation, curative resection, pathological depth of the tumor, and pathological stage of the two groups. Multivariate analyses revealed that the interval between initial gastrectomy and RGC and the pathological TNM stage were significant risk factors for shorter cancer-specific survival. Kaplan-Meier analyses demonstrated that patients with RGC after the five-year follow-up period had a significantly worse prognosis in terms of cancer-specific survival than those who developed RGC within five years. This study suggested surveillance by using the annual endoscopy might be necessary beyond the initial five-year period for patients who underwent gastrectomy for gastric cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.