The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies.

Basolateral CD147 induces hepatocyte polarity loss by E-cadherin ubiquitination and degradation in hepatocellular carcinoma progress

The Adenosine diphosphate-Ribosylation Factor (ARF) family belongs to the RAS superfamily of small GTPases and is involved in a wide variety of physiological processes, such as cell proliferation, motility and differentiation by regulating membrane traffic and associating with the cytoskeleton. Like other members of the RAS superfamily, ARF family proteins are activated by Guanine nucleotide Exchange Factors (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind effectors, which mediate downstream functions. Several studies have reported that cancer cells are able to subvert membrane traffic regulators to enhance migration and invasion. Indeed, members of the ARF family, including ARF-Like (ARL) proteins have been implicated in tumorigenesis and progression of several types of cancer. Here, we review the role of ARF family members, their GEFs/GAPs and effectors in tumorigenesis and cancer progression, highlighting the ones that can have a pro-oncogenic behavior or function as tumor suppressors. Moreover, we propose possible mechanisms and approaches to target these proteins, toward the development of novel therapeutic strategies to impair tumor progression.

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The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective.

Carcinoid of the ampulla of vater

Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions

Adhesion molecules distributed on the cell-surface depends upon their dynamic trafficking that plays an important role during cancer progression. ADP-ribosylation factor 6 (Arf6) is a master regulator of membrane trafficking. CD147, a tumor-related adhesive protein, can promote the invasion of liver cancer. However, the role of Arf6 in CD147 trafficking and its contribution to liver cancer progression remain unclear. Stable liver cancer cell lines with Arf6 silencing and over-expression were established. Confocal imaging, flow cytometry, biotinylation and endomembrane isolation were used to detect CD147 uptake and recycling. GST-pull down, gelatin zymography, immunofluorescence, cell adhesion, aggregation and tight junction formation, Transwell migration, and invasion assays were used to examine the cellular phenotypes. GEPIA bioinformatics, patient’s specimens and electronic records collection, and immunohistochemistry were performed to obtain the clinical relevance for Arf6-CD147 signaling. We found that the endocytic recycling of CD147 in liver cancer cells was controlled by Arf6 through concurrent Rab5 and Rab22 activation. Disruption of Arf6-mediated CD147 trafficking reduced the cell-matrix and cell-cell adhesion, weakened cell aggregation and junction stability, attenuated MMPs secretion and cytoskeleton reorganization, impaired HGF-stimulated Rac1 activation, and markedly decreased the migration and invasion of liver cancer cells. Moreover, high-expression of the Arf6-CD147 signaling components in HCC (hepatocellular carcinoma) was closely correlated with poor clinical outcome of patients. Our results revealed that Arf6-mediated CD147 endocytic recycling is required for the malignant phenotypes of liver cancer. The Arf6-driven signaling machinery provides excellent biomarkers or therapeutic targets for the prevention of liver cancer.

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Arf6-driven endocytic recycling of CD147 determines HCC malignant phenotypes.

Aim To investigate the role of CXC chemokine receptor (CXCR)-7 and CXCL12 in lymph node and liver metastasis of gastric carcinoma. Methods In 160 cases of gastric cancer, the expression of CXCR7 and CXCL12 in tumor and matched tumor-adjacent non-cancer tissues, in the lymph nodes around the stomach and in the liver was detected using immunohistochemistry to analyze the relationship between CXCR7/CXCL12 expression and clinicopathological features and to determine whether CXCR7 and CXCL12 constitute a biological axis to promote lymph node and liver metastasis of gastric cancer. Furthermore, the CXCR7 gene was silenced and overexpressed in human gastric cancer SGC-7901 cells, and cell proliferation, migration and invasiveness were measured by the MTT, wound healing and Transwell assays, respectively. Results CXCR7 expression was up-regulated in gastric cancer tissues (P = 0.011). CXCR7/CXCL12 expression was significantly related to high tumor stage and lymph node (r = 0.338, P = 0.000) and liver metastasis (r = 0.629, P = 0.000). The expression of CXCL12 in lymph node and liver metastasis was higher than that in primary gastric cancer tissues (χ2 = 6.669, P = 0.010; χ2 = 25379, P = 0.000), and the expression of CXCL12 in lymph node and liver metastasis of gastric cancer was consistent with the positive expression of CXCR7 in primary gastric cancer (r = 0.338, P = 0.000; r = 0.629, P = 0.000). Overexpression of the CXCR7 gene promoted cell proliferation, migration and invasion. Silencing of the CXCR7 gene suppressed SGC-7901 cell proliferation, migration and invasion. Human gastric cancer cell lines expressed CXCR7 and showed vigorous proliferation and migratory responses to CXCL12. Conclusion The CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric cancer. CXCR7 is considered a potential therapeutic target for the treatment of gastric cancer.

CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma

Endometrial stromal sarcoma (ESS) is a rare malignant neoplasm of the uterus. We report the first case of undifferentiated ESS (UES) coexistent with grade 1 endometrioid adenocarcinoma in a 73-year-old female who presented with irregular vaginal bleeding for 4 days after menopause 20 years. Imaging examination including Magnetic Resonance Imaging (MRI) demonstrated multi-node reflection in uterine cavity without metastatic lesions, and the endometrium essentially normal. Grossly, a grey-red breakable polypoid tumor of 4.5 × 3.0 ×2.0 cm was recognized in the posterior uterine wall with surrounding slight rough endometrium. Microscopically, the tumor was composed of a larger component of undifferentiated stromal sarcoma that was distinct from a smaller endometrioid adenocarcinoma. The separate components of the tumor could be supported in immunohistochemical studies. There was no sign of recurrence for postoperative 6 months.

Endometrial stromal sarcoma with endometrioid adenocarcinoma of the uterus: a case report.

Neuroendocrine neoplasms (NENs) are generally indolent and progress slowly. However, NENs of major duodenal papilla are uncommon. We retrospectively assessed relevant clinicopathological findings in 9 consecutive patients treated for major duodenal papilla NENs by pancreaticoduodenectomy in our hospital from 2009 to 2013. Eight of the 9 patients (89%) presented with painless obstructive jaundice and one with intermittent fever, attributable to pancreatitis, without jaundice. The diagnostic accuracy was 75% (6/8) for biopsies obtained under duodenoscope guidance. Enhanced multidetector computed tomography detected 89% (8/9) of tumors. Patients with uncertain preoperative diagnoses all underwent intraoperative frozen section pathological diagnosis. Tumor cells extended to at least the muscularis propria in all patients. There were 5 neuroendocrine tumors, 2 neuroendocrine carcinomas, and 2 mixed adenoneuroendocrine carcinomas. Two, 4, and 3 cases were grades 1, 2, and 3, respectively. Grade 3 tumor patients had poor prognoses with tumor recurrence or metastasis within 2 months and all died within 1 year. The overall survival rate (1 year) of grade 3 was lower than in grades 1 and 2 (P .05). To date, only 4 cases of this tumor have been reported in the Chinese literature. The prognosis can be predicted accurately by histopathological features accordingly to the World Health Organization 2010 classification. Multiple imaging techniques and pathological examination should be carried out appropriately to diagnose the disease early.

Neuroendocrine Neoplasms of the Major Duodenal Papilla With Focus on Histopathological Features and Prognosis.

AIM: To investigate if loss of epithelial cell adhesion molecule (EpCAM) is associated with microinvasion in hepatocellular carcinomas (HCCs) in the presence of chronic hepatitis B.

METHODS: The expression of EpCAM, cytokeratin 7 (CK7) and CK19 in 112 hepatic nodules was studied, including 20 HCCs with nodules ≤ 3 cm, 26 HCCs with nodules > 3 cm, 20 high-grade dysplastic nodules, 26 cirrhotic, large regenerative nodules and 20 cases of cirrhosis.

RESULTS: Membranes of ductular reaction (DR) hepatobiliary cells, interlobular bile duct and some hepatic cells were positive for EpCAM expression. Active expression of DR/EpCAM was observed in the majority of noninvasive nodules (50/66, 75.76%); however, expression was absent in the major area of invasion in HCCs (42/46, 91.30%). DR/EpCAM loss in HCCs ≤ 3 cm was higher than in high-grade dysplastic nodules (HGDNs) (P 3 cm, 20 HGDNs) with DR/EpCAM expression had a higher overall survival rate (P 0.05). The diagnostic specificity and diagnostic accuracy were both increased when DR/EpCAM, DR/CK7 and DR/CK19 were combined (P < 0.01).

CONCLUSION: DR/EpCAM loss may be a useful marker for determining microinvasion in HCCs ≤ 3 cm, but also for predicting prognosis.

Zhe Ma

Papers

Arf6-driven endocytic recycling of CD147 determines HCC malignant phenotypes.

CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma

Endometrial stromal sarcoma with endometrioid adenocarcinoma of the uterus: a case report.

Neuroendocrine Neoplasms of the Major Duodenal Papilla With Focus on Histopathological Features and Prognosis.

Perinodular ductular reaction/epithelial cell adhesion molecule loss in small hepatic nodules