Insulin-like growth factors are essential to prevent anoikis in oestrogen-responsive breast cancer cells: importance of the type I IGF receptor and PI3-kinase/Akt pathway.
TL;DR: Because IGF-dependent evasion of anoikis will facilitate metastasis by malignant breast cancer cells, effective inhibition of IGF signal transduction should be included in combinations of targeted drugs designed to treat metastatic oestrogen receptor-positive breast cancers.
Abstract: Detachment of epithelial cells from the extracellular matrix initiates programmed cell death by a process termed anoikis. Malignant cells must acquire anoikis resistance to leave the primary tumour and metastasise. Multiple signal transduction pathways can activate anoikis and confer anoikis resistance, but these are not understood in breast cancer. Models for anoikis of oestrogen-responsive breast cancer cells were established and the protective effects of IGF-1 tested. Cleaved PARP was measured by western transfer and cleaved caspase 3 by flow cytometry. Pathways involved in anoikis and in anoikis resistance were investigated with PI3-kinase, Akt, and MEK1 and MEK2 inhibitors. The importance of the type I IGF receptor was investigated by IGF-concentration dependence, siRNA knockdown and pharmacological inhibition. Association between IGF-1R expression and relapse with distant metastasis was analysed in 1609 patients by log rank test. Unattached breast cancer cells required culture in serum-free medium to induce anoikis. Rapid loss of FAK, Akt and Bad phosphorylation was concurrent with anoiks induction, but ERK1 and ERK2 phosphorylation increased which suggested that anoikis resistance is mediated by the PI3-kinase/Akt rather than the Grb2/Ras/MAP-kinase pathway. IGF-1 conferred anoikis resistance in serum-free medium. IGF-1 activated the PI3-kinase/Akt and Grb2/Ras/MAP-kinase pathways but experiments with PI3-kinase, Akt and MEK1 and MEK2 inhibitors showed that IGF protection is via the PI3-kinase/Akt pathway. The concentration dependence of IGF protection, knockdown experiments with siRNA and pharmacological inhibition with figitumumab, showed that IGF-1 signals through the type I IGF receptor. The crucial role of the type I IGF receptor was demonstrated by induction of anoikis in full serum by figitumumab. High IGF-1R expression was associated with reduced time to relapse with distant metastases in oestrogen receptor-positive patients, especially those with aggressive disease which confirms its relevance in vivo. Anoikis resistance of oestrogen-responsive breast cancer cells depends upon IGF activation of the type I IGF receptor and PI3-kinase/Akt pathway. Because IGF-dependent evasion of anoikis will facilitate metastasis by malignant breast cancer cells, effective inhibition of IGF signal transduction should be included in combinations of targeted drugs designed to treat metastatic oestrogen receptor-positive breast cancers.
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TL;DR: The current understanding of the complex signaling pathways underlying these multiple factors involved in the obesity/diabetes-breast cancer link are discussed, with a focus particularly on the roles of the insulin/IGF system and dyslipidemia in preclinical breast cancer models.
Abstract: The rates of obesity and diabetes are increasing worldwide, whereas the age of onset for both obesity and diabetes are decreasing steadily. Obesity and diabetes are associated with multiple factors that contribute to the increased risk of a number of different cancers, including breast cancer. These factors are hyperinsulinemia, elevated IGFs, hyperglycemia, dyslipidemia, adipokines, inflammatory cytokines, and the gut microbiome. In this review, we discuss the current understanding of the complex signaling pathways underlying these multiple factors involved in the obesity/diabetes-breast cancer link, with a focus particularly on the roles of the insulin/IGF system and dyslipidemia in preclinical breast cancer models. We review some of the therapeutic strategies to target these metabolic derangements in cancer. Future research directions and potential therapeutic strategies are also discussed.
120 citations
TL;DR: In this paper, a review of the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis is presented, which could help to counteract tumor progression and prevent metastasis.
Abstract: The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure-function stability and well-being ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through "anoikis" However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis
71 citations
TL;DR: It is demonstrated that NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) generation are upregulated in suspension gastric cell cultures compared with adherent cultures and induction of NOX4 expression by detachment promotes anoikis resistance of gastric cancer through ROS generation and downstream upregulation of EGFR.
Abstract: Anoikis is a type of programmed cell death induced by detachment from the extracellular matrix. In cancer cells, anoikis resistance is essential for cancer cell survival in blood circulation and distant metastasis. However, the mechanisms behind anoikis resistance of gastric cancer remain largely unknown. Herein, we demonstrate that NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) generation are upregulated in suspension gastric cell cultures compared with adherent cultures. Silencing of NOX4 decreases ROS generation and downregulates EGFR, sensitizing cells to anoikis. NOX4 overexpression upregulates ROS and EGFR levels and promotes anoikis resistance. NOX4 depletion inhibits gastric cancer survival in blood circulation and attenuates distant metastasis. NOX4 expression is correlated with EGFR expression in patients. In conclusion, induction of NOX4 expression by detachment promotes anoikis resistance of gastric cancer through ROS generation and downstream upregulation of EGFR, which is critical for the metastatic progression of gastric cancer.
50 citations
TL;DR: This review analyzes studies published to date about novel small-molecule kinase inhibitors against various malignancies and evaluates if they would be useful to develop new treatment strategies for breast cancer patients.
Abstract: With 1.67 million new cases and 522,000 deaths in the year 2012, breast cancer is the most common type of diagnosed malignancy and the second leading cause of cancer death in women around the world. Despite the success of screening programs and the development of adjuvant therapies, a significant percentage of breast cancer patients will suffer a metastatic disease that, to this day, remains incurable and justifies the research of new therapies to improve their life expectancy. Among the new therapies that have been developed in recent years, the emergence of targeted therapies has been a milestone in the fight against cancer. Over the past decade, many studies have shown a causal role of protein kinase dysregulations or mutations in different human diseases, including cancer. Along these lines, cancer research has demonstrated a key role of many protein kinases during human tumorigenesis and cancer progression, turning these molecules into valid candidates for new targeted therapies. The subsequent discovery and introduction in 2001 of the kinase inhibitor imatinib, as a targeted treatment for chronic myelogenous leukemia, revolutionized cancer genetic pathways research, and lead to the development of multiple small-molecule kinase inhibitors against various malignancies, including breast cancer. In this review, we analyze studies published to date about novel small-molecule kinase inhibitors and evaluate if they would be useful to develop new treatment strategies for breast cancer patients.
44 citations
Cites background from "Insulin-like growth factors are ess..."
...Besides, since PI3K/Akt/mTOR pathway activation has also been related to cell proliferation, survival, adhesion, migration, invasion, altered metabolism, deregulated apoptosis, angiogenesis [54,55], anoikis [56], as well as to breast cancer progression and response to therapy [55,57], this pathway has become one of the main targets to restore the sensitivity of resistant breast tumors....
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20 Sep 2017
TL;DR: Interestingly, for patient samples the predicted tumor growth response correlates with high growth factor expression in the tumor microenvironment, which argues for a co-evolution of both factors in vivo, and might enable a more robust patient stratification in the future.
Abstract: Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great benefit in unselected patient populations. Using an approach of applying Bagged Decision Trees (BDT) to high-dimensional signaling features derived from a computational model, we can predict ligand dependent proliferation across a set of 58 cell lines. This mechanistic, multi-pathway model that features receptor heterodimerization, was trained on seven cancer cell lines and can predict signaling across two independent cell lines by adjusting only the receptor expression levels for each cell line. Interestingly, for patient samples the predicted tumor growth response correlates with high growth factor expression in the tumor microenvironment, which argues for a co-evolution of both factors in vivo.
41 citations
Cites background from "Insulin-like growth factors are ess..."
...The low response rate to IGF-1 in this proliferation screen may reflect the presence of IGF-1 in the low-serum medium and the modest absolute inhibition point to the importance of IGF-1 mediated signaling for survival rather than for proliferation.(26) We and others observed a generally weaker MAPK activation via IGF-1R (see Fig....
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References
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TL;DR: One such compound, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, LY294002, completely and specifically abolished PtdIns 3-kinase activity, which may be beneficial in the treatment of proliferative diseases as well as in elucidating the biological role of the kinase in cellular proliferation and growth factor response.
3,349 citations
"Insulin-like growth factors are ess..." refers methods in this paper
...The importance of the PI3-kinase/Akt pathway in the IGFdependent anoikis resistance was tested with LY294002, a selective, reversible inhibitor of ATP binding in the catalytic subunit of PI3-kinase [28, 29]....
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TL;DR: It is demonstrated that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix, and the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.
Abstract: Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell-matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis." Overexpression of bcl-2 protected cells against anoikis. Cellular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HT1080 cells or v-Ha-ras-transformed MDCK cells by reverse-transformation with adenovirus E1a; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.
3,134 citations
"Insulin-like growth factors are ess..." refers methods in this paper
...The non-ionic acid poly(2-hydroxyethyl methacrylate) (polyHEMA; SIGMA) which inhibits matrix deposition and cell attachment [26] was dissolved in 99 % ethanol at 10 mgml....
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...MCF-7 cells were added to uncoated or poly-HEMAcoated culture wells to prevent cell attachment [26]....
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TL;DR: The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.
3,064 citations
Additional excerpts
...Pathways involved in anoikis and in anoikis resistance were investigated with PI3-kinase, Akt, and MEK1 and MEK2 inhibitors....
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...Signal transduction from the activated receptor is depicted through IRS-1 via the PI3-kinase, PIP3, mTOR2, PDPK1 and Akt pathway (pink) or the Grb2, SOS, Ras, Raf, MEK1 and MEK2, ERK1 and ERK2 pathway (purple)....
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...IGF1 overcomes the cell death signal induced by inhibition of MEK1 and MEK2 without an increase in MAPkinase phosphorylation....
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...Although ERK1 and ERK2 are not important in IGF-dependent anoikis-resistance, IGF-1 is able to circumvent apoptosis induced by inhibition of MEK1 and MEK2 without any increase in MAP-kinase phosphorylation....
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...IGF-1 activated the PI3-kinase/Akt and Grb2/Ras/MAP-kinase pathways but experiments with PI3-kinase, Akt and MEK1 and MEK2 inhibitors showed that IGF protection is via the PI3-kinase/Akt pathway....
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TL;DR: Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastasis cells.
Abstract: Metastasis to distant organs is an ominous feature of most malignant tumours but the natural history of this process varies in different cancers. The cellular origin, intrinsic properties of the tumour, tissue affinities and circulation patterns determine not only the sites of tumour spread, but also the temporal course and severity of metastasis to vital organs. Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastatic cells.
2,403 citations
"Insulin-like growth factors are ess..." refers background in this paper
...Metastatic malignant cells accrue a plethora of characteristics in distinct phases: metastasis initiation, progression and virulence [5]....
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...Breast cancer cells must become resistant to anoikis as they invade breast and surrounding tissue, intravasate into blood and lymphatic vessels and metastasise [5]....
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TL;DR: Interestingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations.
1,140 citations
"Insulin-like growth factors are ess..." refers methods in this paper
...The importance of the PI3-kinase/Akt pathway in the IGFdependent anoikis resistance was tested with LY294002, a selective, reversible inhibitor of ATP binding in the catalytic subunit of PI3-kinase [28, 29]....
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