scholarly journals Stem-like tumor cells involved in heterogeneous vasculogenesis in breast cancer

2020 ◽  
Vol 27 (1) ◽  
pp. 23-39 ◽  
Author(s):  
Yuling Mao ◽  
Liuqing Zhu ◽  
Zhijian Huang ◽  
Chuanghua Luo ◽  
Ti Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Antiangiogenic Therapy ◽  
Vasculogenic Mimicry ◽  
Angiogenesis Inhibitor ◽  
Tube Formation ◽  
Phase Iii

Sorafenib, a small-molecule tyrosine kinase inhibitor with antiangiogenic activity, has been used in liver cancer and kidney cancer treatments. However, clinical trials with sorafenib for breast cancer were stopped in phase III due to limited efficacy. The existence of heterogeneous vasculatures involving tumor cells, such as vessel-like structures formed by vasculogenic mimicry and mosaic vessels, and their resistance to antiangiogenic therapy are thought to be a possible reason for failure of sorafenib therapy. Nevertheless, the features and mechanism of vasculogenesis by tumor cells remain unclear. In the present study, we found that breast cancer stem-like cells (BCSLCs, ALDH1+ cells) were involved in vasculogenic mimicry and mosaic vessel formation in triple-negative breast cancer tissues. Further, only ALDH1+ BCSLCs sorted from MDA-MB-231 could exhibit the tube formation and angiogenesis ability. Sorafenib could inhibit vascularization from endothelial cells rather than that from ALDH1+ cells. α-SMA was identified as a key molecule in vascular formation of BCSLCs. Mechanistically, HIF-1α enhanced the mRNA and protein levels of α-SMA by binding to the HRE element in the promoter directly and meanwhile increased the BCSLCs population. Interestingly, pigment epithelium-derived factor (PEDF), an endogenous angiogenesis inhibitor, could inhibit both endothelial cell-derived and tumor cell-derived angiogenesis by downregulating HIF-1α in breast cancer. Our finding clarified the possible reason for the poor outcome of anti-angiogenesis therapy and PEDF may have the therapeutic potential.

scholarly journals Vasculogenic Mimicry in Breast Cancer: Clinical Relevance and Drivers

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1758
Author(s):  
Gabriela Morales-Guadarrama ◽  
Rocío García-Becerra ◽  
Edgar Armando Méndez-Pérez ◽  
Janice García-Quiroz ◽  
Euclides Avila ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Clinical Relevance ◽  
Antiangiogenic Therapy ◽  
Vasculogenic Mimicry ◽  
Clinicopathological Parameters ◽  
Her2 Positive ◽  
Channel Network ◽  
Tumor Neovascularization

In solid tumors, vasculogenic mimicry (VM) is the formation of vascular structures by cancer cells, allowing to generate a channel-network able to transport blood and tumor cells. While angiogenesis is undertaken by endothelial cells, VM is assumed by cancer cells. Besides the participation of VM in tumor neovascularization, the clinical relevance of this process resides in its ability to favor metastasis and to drive resistance to antiangiogenic therapy. VM occurs in many tumor types, including breast cancer, where it has been associated with a more malignant phenotype, such as triple-negative and HER2-positive tumors. The latter may be explained by known drivers of VM, like hypoxia, TGFB, TWIST1, EPHA2, VEGF, matrix metalloproteinases, and other tumor microenvironment-derived factors, which altogether induce the transformation of tumor cells to a mesenchymal phenotype with a high expression rate of stemness markers. This review analyzes the current literature in the field, including the participation of some microRNAs and long noncoding RNAs in VM-regulation and tumorigenesis of breast cancer. Considering the clinical relevance of VM and its association with the tumor phenotype and clinicopathological parameters, further studies are granted to target VM in the clinic.

IL-33/ST2 Axis Regulates Vasculogenic Mimicry via ERK1/2-MMP-2/9 Pathway in Melanoma

Dermatology ◽  
2019 ◽  
Vol 235 (3) ◽  
pp. 225-233 ◽  
Author(s):  
Fuhan Yang ◽  
Mingming Wen ◽  
Dayu Pan ◽  
Xian Lin ◽  
Jing Mo ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Vasculogenic Mimicry ◽  
Melanoma Cells ◽  
Tube Formation ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Inflammatory Factor ◽  
Action Methods ◽  
Significant Health

Background: Melanoma, an extremely malignant form of cancer, poses a significant health risk. Vasculogenic mimicry (VM), blood vessels formed by tumor cells instead of endothelial cells, is an important factor for the rapid progression of melanoma. Interleukin (IL)-33 is an inflammatory factor commonly found in the tumor microenvironment and plays an important role in the progression of many tumors. IL-33 acts on immune cells and tumor cells through its receptor ST2. This study hypothesized that IL-33 directly affects the progression of melanoma. Objectives: This study was designed to investigate the effect of IL-33 on VM of melanoma and its potential mechanism of action. Methods: The expression of ST2 was evaluated in 66 cases of melanoma collected from human patients, and the differences were analyzed. In vitro experiments were conducted to study the effects of the IL-33/ST2 axis on cell migration and invasion and to elucidate possible mechanisms. Results: ST2 expression is associated with that of matrix metalloproteinase (MMP)-2 and VM in melanoma of patients. IL-33 increases the abilities of proliferation, migration and invasion of melanoma cells and VM tube formation through ST2. IL-33 induces the production of MMP-2/9 via ERK1/2 phosphorylation. Conclusion: IL-33 can directly act on melanoma cells and promote its development.

scholarly journals Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

2020 ◽  
Vol 38 (27) ◽  
pp. 3138-3149 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Shang-Wen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
End Points ◽  
Cns Disease

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

scholarly journals The Brain Penetrating and Dual TORC1/TORC2 Inhibitor, RES529, Elicits Anti-Glioma Activity and Enhances the Therapeutic Effects of Anti-Angiogenetic Compounds in Preclinical Murine Models

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1604 ◽  
Author(s):  
Giovanni Luca Gravina ◽  
Andrea Mancini ◽  
Alessandro Colapietro ◽  
Simona Delle Monache ◽  
Roberta Sferra ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Kinase Inhibitor ◽  
Vasculogenic Mimicry ◽  
Disease Free Survival ◽  
Therapeutic Effects ◽  
Murine Models ◽  
Tubule Formation

Background. Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized tumor and as such, chemotherapy and anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual TORC1/TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-VEGF blocking antibody, bevacizumab, or the tyrosine kinase inhibitor, sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after bevacizumab or sunitinib administration in vivo. Combination strategies were associated with reduced tumor progression as indicated by the analysis of Time to Tumor Progression (TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of tumor bearing mice. RES529 was able to reduce the in vitro migration of tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.

A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
C. Sweeney ◽  
C. Verschraegen ◽  
G. Chiorean ◽  
F. Lee ◽  
S. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Curative Therapy ◽  
Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

Evaluation of prevalence, number, and temporal changes of circulating tumor cells as assessed after 2 and 5 years of follow-up in patients with early breast cancer in the SUCCESS A study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11042-11042 ◽  
Author(s):  
Emanuel C. A. Bauer ◽  
Julia Katharina Neugebauer ◽  
Ulrich Andergassen ◽  
Bernadette Jaeger ◽  
Julia Kathrin Jueckstock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Early Breast Cancer ◽  
Disease Free Survival ◽  
Primary Diagnosis ◽  
Temporal Changes ◽  
Phase Iii ◽  
Time Points

11042 Background: Recent studies revealed that temporal changes in circulating tumor cells (CTC) prevalence assessed before and immediately after adjuvant chemotherapy (CT) might indicate treatment response in early breast cancer (EBC). However, there is limited knowledge on CTC status one or more years after chemotherapy treatment. Here we present descriptive data on CTC status prospectively evaluated 2 and 5 years after primary diagnosis in the German SUCCESS A study. Methods: The SUCCESS A trial is a large, randomized, open-label, 2x2 factorial design Phase III study comparing disease free survival (DFS) in patients with EBC treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC) followed by either 3 cycles of Docetaxel (D) or 3 cycles of Gemcitabine-Docetaxel (DG), and comparing DFS in patients treated with 2 years or 5 years of Zoledronate. CTC status at various time points was assessed using the FDA-approved CellSearch System (Veridex, USA). Results: Data on CTC status both at 2 years and at 5 years after primary diagnosis were available for 983 (26.2%) out of 3754 randomized patients. After 2 and 5 years, CTCs were found in 132 (13.4%; median 1; range 1 – 99) and 88 (9.0%; median 1; range 1 – 60) patients, respectively. The majority of patients (n = 779; 79.2%) had no CTCs at any of the two time points. CTCs were found at 2 years but not at 5 years after primary diagnosis in 116 (11.8%) patients, at 5 years but not at 2 years of follow-up in 72 (7.3%) patients, and both at 2 and at 5 years of follow-up in 16 (1.6%) patients. Conclusions: CTCs in peripheral blood were detected in a subset of early breast cancer patients without relapse up to five years after primary diagnosis. These CTCs may indicate the presence of occult “dormant” micrometastases.

Therapeutic Potential of Melatonin in the Regulation of MiR-148a-3p and Angiogenic Factors in Breast Cancer

MicroRNA ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 237-247 ◽  
Author(s):  
Jéssica Zani Lacerda ◽  
Lívia Carvalho Ferreira ◽  
Beatriz Camargo Lopes ◽  
Andrés Felipe Aristizábal-Pachón ◽  
Marcio Chaim Bajgelman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Real Time ◽  
Tumor Cells ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Gene And Protein Expression

Background: The high mortality rate of breast cancer is related to the occurrence of metastasis, a process that is promoted by tumor angiogenesis. MicroRNAs are small molecules of noncoding mRNA that play a key role in gene regulation and are directly involved in the progression and angiogenesis of various tumor types, including breast cancer. Several miRNAs have been described as promoters or suppressors angiogenesis and may be associated with tumor growth and metastasis. Melatonin is an oncostatic agent with a capacity of modifying the expression of innumerable genes and miRNAs related to cancer. Objective: The aim of this study was to evaluate the role of melatonin and the tumor suppressor miR- 148a-3p on angiogenesis of breast cancer. Method: MDA-MB-231 cells were treated with melatonin and modified with the overexpression of miR-148a-3p. The relative quantification in real-time of miR-148a-3p, IGF-IR and VEGF was performed by real-time PCR. The protein expression of these targets was performed by immunocytochemistry and immunohistochemistry. Survival, migration and invasion rates of tumor cells were evaluated. Finally, the xenograft model of breast cancer was performed to confirm the role of melatonin in the tumor. Results: The melatonin was able to increase the gene level of miR-148a-3p and decreased the gene and protein expression of IGF-1R and VEGF, both in vitro and in vivo. In addition, it also had an inhibitory effect on the survival, migration and invasion of breast tumor cells. Conclusion: Our results confirm the role of melatonin in the regulation of miR-148a-3p and decrease of angiogenic factors.

Pharmacodynamic monitoring of DNA damage biomarkers in circulating tumor cells (CTCs) to assess the mechanism of action of the topoisomerase-1 (Topo1) inhibitor, NKTR-102.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13577-e13577
Author(s):  
Sujita Sukumaran ◽  
Christopher Neal ◽  
Jacky Woo ◽  
Vladislava O. Melnikova ◽  
Kenna Lynn Anderes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Protein Expression ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Phase Iii ◽  
Continuous Exposure ◽  
Dose Dependent Increase ◽  
Dose Dependent

e13577 Background: Inhibitors of Topo1 abrogate DNA replication and induce apoptosis in tumor cells. Topo1 inhibitors are effective cancer therapeutics however improved pharmacokinetic profiles have been sought. NKTR-102 is a next generation topoisomerase I-inhibitor with a unique pharmacokinetic profile that provides continuous exposure of the active metabolite, SN38. NKTR-102 is in phase III clinical development for patients with metastatic breast cancer. Monitoring DNA damage response markers in CTCs may be an informative, minimally invasive approach to detect drug activity in patients. Objectives of this study are to: 1) develop a multiplex immunofluorescent assay for measuring DNA damage effects of SN38 in CTCs; 2) obtain data to determine whether measuring DNA damage biomarkers in CTCs isolated from blood of cancer patients treated with SN38 ex vivo could be applied clinically to identify the best responders to NKTR-102. Methods: Solid tumor cell lines were treated with SN38 for 24 hr. Expression levels of gH2AX, survivin, BRCA1, BRCA2, RAD51, ATM and TUNEL were measured by quantitative laser scanning cytometry (LSC).Cytotoxcity was confirmed by MTT assay. Blood samples from 3 cancer patients were treated ex vivo with SN38 and CTCs were recovered and analyzed for expression of DNA damage biomarkers by LSC. Results: Treatment of H460 and HCT116 cells with SN38 led to a dose-dependent increase in the level of protein expression and/or frequency of positive cells for all DNA damage markers. Ex vivo treatment of breast cancer patients' blood with SN38 for 24 hr induced a dose-dependent increase in the expression of ATM (7.8-fold) and RAD51(188-fold) in one patients’ blood sample. An increase in the percent TUNEL-positive cells (0-20% in untreated to 44-54% in drug-treated samples) was observed in 2 patients’ samples without affecting the total number of isolated CTCs. Conclusions: Quantitative multiplex immunofluorescent assays for monitoring changes in gH2AX, ATM, RAD51 protein expression and percent TUNEL positive CTCs have been developed using LSC. These assays have been incorporated into an ongoing phase III clinical study of NKTR-102.

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