Osteopontin induces multiple changes in gene expression that reflect the six “hallmarks of cancer” in a model of breast cancer progression

Cook, Amy C.; Tuck, Alan B.; McCarthy, Susan; Turner, Joel G.; Irby, Rosalyn; Bloom, Gregory; Yeatman, Timothy J.; Chambers, Ann F.

doi:10.1002/mc.20105

Cited by 93 publications

(88 citation statements)

References 38 publications

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“…Here we show that TT cells overexpressing OPNa, OPNb and OPNc show a significant decrease in proliferation and viability, being OPNa isoform having the most prominent effect. Although OPN is widely known as implicated in promoting invasive and metastatic progression in many carcinomas (11,57), in medullary thyroid cancer, the overexpression of OPN isoforms seems to be related with a protective role, as reported in pancreatic adenocarcinoma (58). These results indicate that in MTC, OPN contributes to impair tumour growth, corroborating the hypothesis that OPN can act in the maintenance of the differentiation of C-cells.…”

Section: Discussionsupporting

confidence: 76%

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

Ferreira¹,

Eloy²,

Pestana³

et al. 2016

European Journal of Endocrinology

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Background: Osteopontin (OPN) or secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and has been shown to be involved in tumourigenesis and metastasis in many malignancies, including follicular cell-derived thyroid carcinomas. Its role in C-cell-derived thyroid lesions and tumours remains to be established. Objective: The objective of this study is to clarify the role of OPN expression in the development of medullary thyroid carcinoma (MTC). Methods: OPN expression was analysed in a series of 116 MTCs by immunohistochemistry and by qPCR mRNA quantification of the 3 OPN isoforms (OPNa, OPNb and OPNc) in six cases from which fresh frozen tissue was available. Statistical tests were used to evaluate the relationship of OPN expression and the clinicopathological and molecular characteristics of patients and tumours. Results: OPN expression was detected in 91 of 116 (78.4%) of the MTC. We also observed high OPN expression in C-cell hyperplasia as well as in C-cells scattered in the thyroid parenchyma adjacent to the tumours. OPN expression was significantly associated with smaller tumour size, PTEN nuclear expression and RAS status, and suggestively associated with non-invasive tumours. OPNa isoform was expressed significantly at higher levels in tumours than in non-tumour samples. OPNb and OPNc presented similar levels of expression in all samples. Furthermore, OPNa isoform overexpression was significantly associated with reduced growth and viability in the MTC-derived cell line (TT). Conclusion: The expression of OPN in normal C-cells and C-cell hyperplasia suggests that OPN is a differentiation marker of C-cells, rather than a marker of biological aggressiveness in this setting. At variance with other cancers, OPN expression is associated with good prognostic features in MTC.

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Section: Discussionsupporting

confidence: 76%

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

Ferreira¹,

Eloy²,

Pestana³

et al. 2016

European Journal of Endocrinology

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“…OPNc could stimulate growth signal autonomy by different strategies, such as alteration of extracellular growth signals, of transcellular transducers of those signals or of intracellular circuits that translates those signals into action (26). Literature has provided evidence that total OPN affect the expression of genes involved in multiple aspects of tumor progression and malignant growth, including those involved on self-sufficiency in growth signals (42,43). In ovarian carcinoma, among all isoforms, OPNc could better stimulate these signals as compared with the remaining isoforms.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Tilli

Franco²,

Robbs³

et al. 2011

Molecular Cancer Research

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Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression. Mol Cancer Res; 9(3); 280-93. Ó2011 AACR.

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“…36 These cells were maintained in culture in a-MEM supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine (both from Gibco Life Technologies, Grand Island, NY, USA), insulin (1 mg/ml), epidermal growth factor (12.5 ng/ml), hydrocortisone (2.8 mM), 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 1 mM sodium pyruvate, 0.1 mM non-essential amino acids and 50 mg/mL gentamycin reagent (all from Sigma Chemical, St Louis, MO, USA), as previously described. 39 After addition of all reagents, this growth medium was referred to as aHE. The 21PT and 21NT-derived cell lines used in this work, designated 21PTci and 21NTci, contain an empty neoselection vector and have been used as control cell lines for previous work in our laboratory.…”

Section: Materials and Methods Cell Lines And Culturementioning

confidence: 99%

Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns

Souter

Andrews

Cook

et al. 2010

Laboratory Investigation

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Early breast cancer progression involves advancement through specific morphological stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not necessarily always in a linear fashion. Observational studies have examined genetic, epigenetic and gene expression differences in breast tissues representing these stages of progression, but model systems which would allow for experimental testing of specific factors influencing transition through these stages are scarce. The 21T series cell lines, all originally derived from the same patient with metastatic breast cancer, have been proposed to represent a mammary tumor progression series. We report here that three of the 21T cell lines indeed mimic specific stages of human breast cancer progression (21PT-derived cells, ADH; 21NT-derived cells, DCIS; 21MT-1 cells, IMC) when grown in the mammary fat pad of nude mice, albeit after a year. To develop a more rapid, readily manipulatable in vitro assay for examining the biological differences between these cell lines, we have used a 3D Matrigel system. When the three cell lines were grown in 3D Matrigel, they showed characteristic morphologies, in which quantifiable aspects of stage-specific in vivo behaviors (ie, differences in acinar structure formation, cell polarization, colony morphology, cell proliferation, cell invasion) were recapitulated in a reproducible fashion. Gene expression profiling revealed a characteristic pattern for each of the three cell lines. Interestingly, Wnt pathway alterations are particularly predominant in the early transition from 21PTci (ADH) to 21NTci (DCIS), whereas alterations in expression of genes associated with control of cell motility and invasion phenomena are more prominent in the later transition of 21NTci (DCIS) to 21MT-1 (IMC). This system thus reveals potential therapeutic targets and will provide a means of testing the influences of identified genes on transitions between these stages of pre-malignant to malignant growth. KEYWORDS: breast cancer; tumor progression; expression microarray; atypical ductal hyperplasia; ductal carcinoma in situ; invasive mammary carcinoma Pathological and epidemiological evidence has led to a histological model of breast cancer evolution, in which stem cells from the terminal duct lobular unit give rise to atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia, which can then progress to ductal carcinoma in situ (DCIS) or lobular carcinoma in situ, respectively, and eventually to invasive mammary carcinomas (IMC).1-6 These histological patterns are, however, most likely only rough phenotypic indications of underlying cellular and molecular events determining progression, 7 and may not necessarily occur in a linear fashion. There is currently much interest in identifying the nature of the cellular and molecular events involved, not only for use in determining at which point a lesion is most likely to progress to malignancy, but also in hopes of finding a way to halt ...

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Osteopontin induces multiple changes in gene expression that reflect the six “hallmarks of cancer” in a model of breast cancer progression

Cited by 93 publications

References 38 publications

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns

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