Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs.

Antiangiogenic tyrosine kinase inhibitors (AA-TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA-TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA-TKI therapy withdrawal-induced tumour revascularization frequently occurs, hampering the clinical application of AA-TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA-TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA-TKI cessation experimental settings. Mechanistically, tumour perivascular cell-derived extracellular vehicles (TPC-EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off-AA-TKI-induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long-lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.

Rheb/mTOR/p70s6k Cascade and TFE3 Expression in Conventional and Sclerosing PEComas of the Urinary Tract.

Perivascular epithelioid cell tumors (PEComas) are rarely found in the urinary tract. The clinicopathologic characteristics of 10 cases, retrospectively collected from 5 medical institutions in 3 different European countries, are presented in this study. Male/female ratio was 3:7 and the average age at diagnosis was 62.7 years. Nine cases were sporadic and 1 showed germline mutation of the TSC2 gene. Eight cases were located in the kidney, 1 in the left adrenal and 1 in the right ureter. All of the patients were alive and free of disease at the time of last contact (mean follow-up, 14.1 mo). Four cases displayed a conventional morphology and 6 showed a prominent sclerotic stroma. By immunohistochemistry, melanocytic markers were consistently expressed, especially HMB-45 (10 cases), MiTF (9 cases), and Melan-A (6 cases). Desmin was expressed in 6 cases; 2 cases were positive for CD117; a single case showed TFE3 expression. pMAPK, mTOR, and pAKT demonstrated variable immunostaining with focal positivity in 7, 4, and 2 cases, respectively. Cytokeratins were repeatedly negative in all cases. PEComas in the urinary tract, especially in the renal region, may show a relatively high frequency of the sclerosing histologic subtype. Knowledge of the distinct histology and immunohistochemical profile is vital to correctly diagnose this rare entity.

Acute abdomen as an unusual presentation of hepatic PEComa. A case report.

Perivascular epithelioid cell (PEC) tumors (or PEComas) are myomelanocytic lesions defined by coexpression of melanocytic and muscle markers, suggesting dual differentiation. They are rare mesenchymal tumors and include subtypes with distinct clinical features: angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumors of the lung, pancreas and uterus. Consequent upon the World Health Organization's recognition of PEC-derived tumors as a distinct entity, an increasing number of reports has documented PEComas arising at various anatomical locations. Clear cell myomelanocytic tumors of the falciform ligament/ligamentum teres (CCMTs) represent a rare variant of the PEComas. These hepatic PEComas, different from angiomyolipoma of the liver, pose a clinical, radiological and morphological diagnostic challenge. Because of their rarity, the clinical features and biological behavior of these tumors have yet to be established. We experienced our first case of CCMT in a 36-year-old woman who presented to our emergency department with a 3-day history of abdominal discomfort and progressive growth of an epigastric bulk. Intralesional hemorrhage was causing abdominal distension, which progressed to acute abdomen soon after. The hemoglobin concentration was 9.9 g/dL. Liver laboratory tests showed slight elevation of AST, ALT and gamma-GT. The alpha-fetoprotein level was not elevated. The radiological images showed a hemorrhagic mass with some bizarre features in left hepatic lobe, immediately adjacent to the ligamentum teres and falciform ligament. The patient underwent a left hepatic lobectomy. The diagnosis of CCMT was based on histological and immunohistochemical staining. The postoperative course was uneventful. The patient received no adjuvant treatment and is currently, 34 months after surgery, alive and disease free. In this report we describe a peculiar and hitherto undescribed clinical presentation of this tumor and its further course. Moreover, we discuss previously undescribed diagnostic imaging. We recommend that all unusual carcinomas and mesenchymal tumors of the liver should be tested for HMB-45: when positive, there is a high likelihood of PEComa.