Differential expression of VEGFR2 protein in HER2 positive primary human breast cancer: potential relevance to anti-angiogenic therapies

et al. 2020

Cancer Cell Int

Background: Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood. Materials and methods: Eighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed. Results: We found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/β-catenin pathway. Specifically, apatinib induced the degradation of β-catenin and decreased its transcriptional activity through Akt/GSK-3β repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer. Conclusion: Our study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/β-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.

Section: Discussionmentioning

confidence: 89%

Apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer via the Akt/β-catenin pathway

Wei

et al. 2020

Cancer Cell Int

“…These data imply that the effects of HER2 on tumorigenesis are at least partially mediated by stimulation of angiogenesis, which provides a strong rationale for targeting the VEGF/VEGFR2 axis in HER2-positive breast cancer. 29 Based on this hypothesis, several clinical trials have been conducted to explore the potential benefit of anti-HER2 and anti-angiogenesis combination therapy for HER2-positive breast cancer. Results from early phase trials have been promising.…”

Section: Discussionmentioning

confidence: 99%

Significant response to apatinib monotherapy in heavily pretreated advanced HER2-positive breast cancer: a case report and literature review

Zhang

Cancer Biology & Therapy

et al. 2020

Although HER2-targeted therapy has been shown to prolong the survival of patients with HER2-positive breast cancer, most patients eventually progress due to drug resistance. Novel treatment options are urgently needed to overcome resistance to HER2-targeted therapy. The VEGF/VEGFR (Vascular endothelial growth factor and its receptors) pathway is essential in tumor angiogenesis, which may be a promising target in HER2-positive breast cancer providing a rationale for the use of tyrosine kinase inhibitors (TKIs) targeting VEGFR. Here, we present a case of a heavily pretreated advanced breast cancer patient who did not respond to HER2-targeted therapy and developed resistance to multiple lines of HER2-targeted treatment. The patient was treated with apatinib at a dose of 500 mg daily, and obtained partial remission (PR) with a progression-free-stage (PFS) of 6 months. Our case indicates that apatinib might have anti-tumor activity in patients with HER2-positive breast cancer with HER2-targeted resistance. This case is of value which may provide new insights into strategies for HER2-targeted therapy resistance options in the clinic.

“…Our data showed a higher THC value in Ki67 index-high lesions, alas without statistical significance. With lesion size increasing from Stage T1 to Stages T2 and T3, THC increased along with Ki67 index; but no THC difference was found between T2 and T3 lesions, probably due to saturated blood supply when tumors grow to a certain large size, or to tumor heterogeneity [28] , we speculate. Using multiple regression analysis tool, we derived a formulation of THC = 167.2 + 1.062size+ 0.298ki67, to demonstrate a linear correlation of THC and its 2 most impacting factors lesion size and Ki67 index.…”

Section: Discussionmentioning

confidence: 69%

US-guided Diffuse Optical Tomography: Clinicopathological Features Affect Total Hemoglobin Concentration in Breast Cancer

Zhi

Chang

et al. 2018

Translational Oncology

PURPOSE: To investigate breast cancers total hemoglobin concentration (THC) characteristics and its association with clinical pathologic findings. MATERIALS AND METHODS: The study was approved by the institutional review board and all patients provided written informed consent. 447 breast cancer patients, totally 455 lesions were included in our study. The size and THC of breast lesions were measured by conventional ultrasound (US) and US-guided Diffuse Optical Tomography (DOT) 1–2 days before surgery. Clinical and pathology information of patients was collected. RESULT: The average THC values of ER- or PR- lesions were significantly higher than the positive ones (P = .005 and P = .01,respectively); The average THC values of axillar LN+ or LVI+ were higher than the negative ones (P = .042 and P = .043, respectively). No significant THC difference was found in groups of infiltrating vs. non-infiltrating, HER2+ vs. HER2-, Ki67 high vs. Ki67 low, and different menstrual phases (P = .457, P = .917, P = .417, P = .213, respectively).The incidence ages and the lesion-nipple distances of T3 patients were lower than that of T1 and T2 (P < .001 and P < .001 respectively). The THC values and Ki67 indexes of T2 and T3 lesions were similar, but were higher than that of the T1 group (P < =0.001 and P = .006, respectively). CONCLUSION: Clinicopathological features of breast cancer, such as ER and PR status, axillary lymph node metastasis, lymphovascular invasion, correlate with THC values. Furthermore, the Ki67 indexes can be predicted using tumor size and THC, useful for pre-surgical evaluation of cancer biology and real-time, non-invasive monitoring of NAC efficacy.