Trefoil factor family 1 expression in the invasion front is a poor prognostic factor associated with lymph node metastasis in pancreatic cancer

Sunagawa, Masaki; Yamaguchi, Junpei; Kokuryo, Toshio; Yokoyama, Yukihiro; Sugawara, Gen; Nagino, Masato

doi:10.1016/j.pan.2017.07.188

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…In the present study, the expression of TFF1 was observed to gradually decreased from mucosa to deeper layers, suggesting that the loss or reduction of this protein may confer an invasive phenotype to canine gastric neoplastic cells and thus promote cancer progression. Similar findings were discussed by Sunagawa et al [44] who reported lost or decreased expression of TFF1 in the tumor invasion front of human pancreatic ductal adenocarcinomas (PDAC). Based on these findings, they speculated that the loss of TFF1 resulted in the epithelial-mesenchymal transition (EMT) of tumor cells and, therefore, upregulation of TFF1 might inhibit the EMT in cancer cells.…”

Section: Discussionsupporting

confidence: 87%

Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues

Flores

Castro

Rêma

et al. 2021

Animals

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TFF1 expression is markedly reduced in human GCs, suggesting that TFF1 is a tumor suppressor for human gastric cancer. The present study evaluated the expression and distribution pattern of TFF1 in paraffin-embedded canine gastric tissue samples, including normal mucosa (n = 3), polyps (n = 8), carcinomas (n = 31) and their adjacent non-neoplastic mucosa (n = 30), neoplastic emboli (n = 14), and metastatic lesions (n = 8), by immunohistochemistry (IHC). All normal gastric tissues expressed TFF1 in the superficial foveolar epithelium and mucopeptic cells of the neck region. Most gastric polyps (GPs) displayed immunoreactivity for TFF1 in >75% of the epithelial component. In GCs, the expression of TFF1 was found reduced in 74.2% of the cases. The level of TFF1 expression had a decreased tendency from normal gastric mucosa to GPs and GCs (p < 0.05). No significant differences in the expression of TFF1 were found in GCs, according to age, sex, histological type based on World Health Organization (WHO) and Lauren classification, tumor location, depth of tumor invasion, presence of neoplastic emboli or metastatic lesions. The median survival time of GC patients with preserved and reduced TFF1 immunoexpression were 30 and 12 days, respectively. Kaplan–Meier analysis revealed no significant survival differences between the two groups (p > 0.05). These findings suggest that TFF1 protein may play a role in canine gastric carcinogenesis, and further studies are necessary to define its usefulness as a prognostic indicator in canine gastric carcinoma.

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Section: Discussionsupporting

confidence: 87%

Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues

Flores

Castro

Rêma

et al. 2021

Animals

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“…To investigate the chemosensitivity of human pancreatic cancer, we assessed the expression of TFF1 in surgically resected human pancreatic cancer specimens. As we have reported previously, the positivity rate of TFF1 in pancreatic cancer was almost 80%, and positivity was not associated with the survival rate after curative surgical resection 15 . This result was consistent with the findings of our mouse model showing similar survival of the KPC and KPC/TFF1KO groups.…”

Section: Tff1 Expression Enhances the Chemosensitivity Of Pancreatic ...supporting

confidence: 68%

Trefoil Factor 1 Suppresses Stemness And Enhances Chemosensitivity Of Pancreatic Cancer

Yanaguchi

Kokuryo

Yokoyama

et al. 2022

Preprint

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Pancreatic cancer is one of the most lethal malignancies, partly due to its high resistance to conventional chemotherapy. The aim of this study is to investigate the association between chemoresistance and trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis. To investigate the role of TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/ LSL-KRASG12D/ LSL-p53R172H/ TFF1-/-) were analysed. The expression of TFF1 in cancer cells was associated with better survival of the patients who underwent chemotherapy, and the deficiency of TFF1 increased EMT of cancer cells and deteriorated the benefit of gemcitabine in mice. To explore the efficacy of TFF1 treatment, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines and mouse models. TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells by gemcitabine. Combined treatment of gemcitabine and TFF1 arrested tumor growth and resulted in the better survival of mice. These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.

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“…Nevertheless, TFF1 and TFF2 have been shown to increase PC cell proliferation and migration [24,44]. Moreover, higher TFF1 expression was found in central tumors while decreased expression was observed in the invasion front of human PDAC however, retained TFF1 expression in the invasion front was associated with positive lymphatic invasion, lymph node metastasis and poor survival of PC patients [45]. However, based on our findings and earlier reports, we believe that TFFs are very critical factors in PC pathogenesis and that they warrant precise study with mouse models and in vivo lineage tracing studies.…”

Section: Discussionmentioning

confidence: 99%

Trefoil factor(s) and CA19.9: A promising panel for early detection of pancreatic cancer

et al. 2019

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Background: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC. Methods: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9. Findings: The publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUC TFF1+TFF2+TFF3+CA19.9 = 0.93) as well as CP (AUC TFF1+TFF2+TFF3+CA19.9 = 0.93). Notably, at 90% specificity (desired for blood-based biomarker panel), TFFs combination improved CA19.9 sensitivity by 10% and 25% to differentiate EPC from BC and CP respectively. In an independent blinded validation set, the combination of TFFs and CA19.9 (AUC TFF1+TFF2+TFF3+CA19.9 = 0.82) also improved the overall efficacy of CA19.9 (AUC CA19.9 = 0.66) to differentiate EPC from CP proving unique biomarker capabilities of TFFs to distinguish early stage of this deadly lethal disease. Interpretation: In silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.

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Trefoil factor family 1 expression in the invasion front is a poor prognostic factor associated with lymph node metastasis in pancreatic cancer

Cited by 13 publications

References 34 publications

Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues

Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues

Trefoil Factor 1 Suppresses Stemness And Enhances Chemosensitivity Of Pancreatic Cancer

Trefoil factor(s) and CA19.9: A promising panel for early detection of pancreatic cancer

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