scholarly journals Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jia-Hong Chen ◽  
Wen-Chien Huang ◽  
Oluwaseun Adebayo Bamodu ◽  
Peter Mu-Hsin Chang ◽  
Tsu-Yi Chao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Metastatic Breast Cancer ◽  
Cancer Stem Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Breast ◽  
Mesenchymal Transition ◽  
Monospecific Antibody

scholarly journals The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells

2020 ◽  
Vol 98 (10) ◽  
pp. 1431-1446 ◽  
Author(s):  
Elena Andreucci ◽  
Silvia Peppicelli ◽  
Jessica Ruzzolini ◽  
Francesca Bianchini ◽  
Alessio Biagioni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Melanoma Cells ◽  
Cell Subpopulation ◽  
Mesenchymal Transition ◽  
Extracellular Acidosis

Abstract Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both “aerobic” and “anaerobic” glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-to-mesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosis-induced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor. Key messages • Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells • Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells • Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells • Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells • Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells

scholarly journals RUNX1 suppresses breast cancer stemness and tumor growth

2018 ◽  
Author(s):  
Deli Hong ◽  
Andrew J. Fritz ◽  
Kristiaan H. Finstad ◽  
Mark P. Fitzgerald ◽  
Adam L. Viens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Cancer Stem Cell ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Cell Activity ◽  
Mesenchymal Transition

SummaryRecent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved. We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors.

scholarly journals Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changhu Lee ◽  
Hyung Won Ryu ◽  
Sahee Kim ◽  
Min Kim ◽  
Sei-Ryang Oh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
Bioactive Component ◽  
Metastatic Growth

AbstractBreast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo

2009 ◽  
Vol 120 (1) ◽  
pp. 253-260 ◽  
Author(s):  
Ramon C. Sun ◽  
Mitali Fadia ◽  
Jane E. Dahlstrom ◽  
Christopher R. Parish ◽  
Philip G. Board ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Metastatic Breast ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth

scholarly journals ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sara Charmsaz ◽  
Ben Doherty ◽  
Sinéad Cocchiglia ◽  
Damir Varešlija ◽  
Attilio Marino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
In Silico ◽  
Ex Vivo ◽  
Metastatic Breast ◽  
Peptide Mimetic ◽  
Breast Cancer Brain Metastasis

Abstract Background Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Methods Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Results Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. Conclusion ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

scholarly journals EP300 Knockdown Abrogates Cancer Stem Cell Phenotype, Tumor Growth and Metastasis in Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Alexander Ring ◽  
Pushpinder Kaur ◽  
Julie E. Lang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Side Population ◽  
Tumor Growth And Metastasis

Abstract Background:Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with basal features, lacking the expression of receptors targeted successfully in other breast cancer subtypes. Treatment response to adjuvant and neoadjuvant chemotherapy is often short-lived and metastatic spread occurs at higher rates than other subtypes within the first five years after diagnosis. TNBCs exhibit stem cell features and are enriched for cancer stem cell (CSC) populations. E1A Binding Protein P300(EP300) is a large protein with multiple cellular functions, including as an effector in stem cell biology.Methods: We used a genetic knockdown (KD) model of EP300 in TNBC cell lines to investigate the effect on CSC phenotype, tumor growth and metastasis. Side population assay and tumorsphere suspension culture were used in vitro. Xenograft mouse models were used for in vivo studies. We performedin silico analysis of publicly available gene expression data sets to investigate CSC gene expression and molecular pathways as well as survival outcomes associated with EP300 expression in patients with TNBC and basal-like BC.Results: EP300 KD abolishedthe CSC phenotype by reducing ABCG2 expression, side population cells andtumorsphere formation capacityin vitro as well as tumor formation in a xenograft mouse model in vivo. Metastatic capacity was markedly reduced in EP300 KD cells in vivo, with no detection of circulating tumor cells.TCGA data analysis demonstrated that genes positively correlated with EP300 expression in TNBC and basal-like BC were associated with CSC biology. Survival analysis demonstrated that EP300 expression predicts poor recurrence free survival in TNBC and basal BC. Conclusion:We report a novel oncogenic role for EP300 in driving CSC phenotyperepresentinga potential target to address tumor initiation and metastatic spread in TNBC and basal-like BC. EP300 might serve as a prognostic marker and potential therapeutic target in TNBC.

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