Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

Erratum: Author correction to "The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway" Acta Pharm Sin B 12 (2022) 1288-1304

[This corrects the article DOI: 10.1016/j.apsb.2021.08.015.].

The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

Clinical implications of 3D printing technology in preoperative evaluation of partial nephrectomy / 中南大学学报(医学版)

OBJECTIVES@#Renal cancer is a common malignancy of the urinary system, and the partial nephrectomy is a common surgical modality for early renal cancer. 3D printing technology can create a visual three-dimensional model by using 3D digital models of the patient's imaging data. With this model, surgeons can perform preoperative assessment to clarify the location, depth, and blood supply of the tumor, which helps to develop preoperative plans and achieve better surgical outcomes. In this study, the R.E.N.A.L scoring system was used to stratify patients with renal tumors and to explore the clinical application value of 3D printing technology in laparoscopic partial nephrectomy.@*METHODS@#A total of 114 renal cancer patients who received laparoscopic partial nephrectomy in Xiangya Hospital from June 2019 to December 2020 were enrolled. The patients were assigned into an experimental group (n=52) and a control group (n=62) according to whether 3D printing technology was performed, and the differences in perioperative parameters between the 2 groups were compared. Thirty-nine patients were assigned into a low-complexity group (4-6 points), 32 into a moderate-complexity group (7-9 points), and 43 into a high-complexity group (10-12 points) according to R.E.N.A.L score, and the differences in perioperative parameters between the experimental group and the control group in each score group were compared.@*RESULTS@#The experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (all P<0.05), less intraoperative blood loss (P=0.047), and smaller postoperative blood creatinine change (P=0.032) compared with the control group. In the low-complexity group, there were no statistically significant differences between the experimental group and the control group in operation time, renal ischemia time, intraoperative blood loss, postoperative blood creatinine changes, and postoperative hospital stay (all P>0.05). In the moderate- and high- complexity groups, the experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (P<0.05 or P<0.001), less intraoperative blood loss (P=0.022 and P<0.001, respectively), and smaller postoperative blood creatinine changes (P<0.05 and P<0.001, respectively) compared with the control group.@*CONCLUSIONS@#Compared with renal tumor patients with R.E.N.A.L score<7, renal cancer patients with R.E.N.A.L score≥7 may benefit more from 3D printing assessment before undergoing partial nephrectomy.

Application of retroperitoneal laparoscopic partial nephrectomy for renal cell carcinoma of the early stage / 中南大学学报(医学版)

Objective:To evaluate the feasibility and clinical efficacy of retroperitoneal laparoscopic nephronsparing surgery for renal cell carcinoma of the early stage.Methods:Between June 2003 and June 2008,53 patients (31 males and 22 females) with renal mass were selected to undergo wedge resection of the tumor through retroperitoneal laparoscopy.Spiral computerized tomography (CT) and color Doppler ultrasound were used to provide information for nephron-sparing surgery (NSS).Patients with small (≤3 cm),peripheral,shallow and exophytic tumors,at a distance which exceeded approximately 10 mm between the tumor and renal collecting system,were enrolled into our studies.Surgical resection was performed along a resection line about 0.5 cm from the tumors.Results:All procedures were technically successful.Mean operating time was 96 min (ranging from 75 to 110 min).Mean warm ischemia time was 15 min (ranging from 10 to 21 min).Mean estimated blood loss was 70 m L (ranging from 40 to 120 mL).Mean hospital stay after the surgery was 4.2 days (ranging from 3 to 6 days).No intraoperative or postoperative complications occurred.Of 53 patients,52 had negative surgical margins and a 63-year male patient had a positive surgical margin.Neither local recurrence nor trocar-site metastasis was observed in the 53 patients during followups averaging 39 months (ranging from 11 to 83 months).Conclusion:Under the modified techniques of the surgery and conservative criteria for patient selection,laparoscopic partial nephrectomy can be safely and effectively performed and satisfactory outcomes are achievable.

Anti-angiogenetic effect of arenobufagin in vitro and in vivo / 药学学报

This study is to investigate the anti-angiogenetic effect of arenobufagin in vitro and in vivo. The anti-proliferation effect of arenobufagin on CNE-2, Hep2, SH-SY5Y, LOVO, PC-3 and DU145 cells as well as human umbilical vein endothelial cells (HUVECs) was determined by MTT assay. Cell morphological changes of LOVO and HUVECs after arenobufagin treatment were observed by microscopy. Arenobufagin inhibited the proliferation of CNE-2, Hep2, SH-SY5Y, LOVO, PC-3, DU145 and HUVECs in a dose-dependent manner. Furthermore, it was obviously observed that the subcytotoxic concentration of arenobufagin in human carcinoma cells induced a marked decrease in the viability of HUVECs. Chick embryo chorioallantoic membrane (CAM) model was used to detect the anti-angiogenetic effect of arenobufagin in vivo. Arenobufagin significantly suppressed the angiogenesis of CAM. Cell cycle analysis demonstrated that G2/M phase was arrested and the sub-G1 peak appeared with the increase of arenobufagin concentration. PI/Annexin V double staining assay further demonstrated that arenobufagin could induce apoptosis in a dose- and time-dependent manner. Mitochondrial potential collapse detected by flow cytometric analysis was increased after arenobufagin treatment. It also observed that PARP was cleaved to p85 active form by Western blotting. Taken together, arenobufagin has significant anti-angiogenetic effect in vitro and in vivo, and the action mechanisms behind its anti-angiogenesis may be associated with cell cycle arrest and apoptosis of vein endothelial cells.