Complex interactions between tumor and host cells regulate systemic tumor dissemination, a process that begins early at the primary tumor site and goes on until tumor cells detach themselves from the tumor mass and start migrating into the blood or lymphatic vessels. Metastatic cells colonize the target organs and are capable of surviving and growing at distant sites. In this context, osteopontin (OPN) appears to be a key determinant of the crosstalk between cancer cells and the host microenvironment, which in turn modulates immune evasion. OPN is overexpressed in several human carcinomas and has been implicated in inflammation, tumor progression, and metastasis. Thus, it represents one of the most attracting targets for cancer therapy. Within the tumor mass, OPN is secreted in various forms either by the tumor itself or by stroma cells, and it can exert either pro- or antitumorigenic effects according to the cell type and tumor microenvironment. Thus, targeting OPN for therapeutic purposes needs to take into account the heterogeneous functions of the multiple OPN forms with regard to cancer formation and progression. In this review, we will describe the role of systemic, tumor-derived, and stroma-derived OPN, highlighting its pivotal role at the crossroads of inflammation and tumor progression.

/pdf/osteopontin-at-the-crossroads-of-inflammation-and-tumor-326l6u6ehl.pdf

Osteopontin at the Crossroads of Inflammation and Tumor Progression.

Osteopontin splice variants and polymorphisms in cancer progression and prognosis

Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence Gamma-secretase inhibitor (GSI) is a broad-spectrum Notch inhibitor, but it has serious side effects The efficacy of Notch3-specific inhibition in paclitaxel-resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI To analyze the effect of Notch3-specific inhibition on paclitaxel-resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel-resistant SKpac cells and parental SKOV3 cells Expression levels of survival, cell cycle, and apoptosis-related proteins were measured and compared between groups Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group In paclitaxel-resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel Spheroid formation was also significantly reduced Both Notch3 siRNA-treated cells and GSI-treated cells arrested in the G2/M phase of the cell cycle Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated Both GSI and Notch3 siRNA treatment reduced expression of anti-apoptotic proteins (BCL-W, BCL2, and BCL-XL) and increased expression of pro-apoptotic proteins (Bad, Bak, Bim, Bid, and Bax) These results indicate that Notch3-specific inhibition sensitizes paclitaxel-resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI This approach would be likely to avoid the side effects of broad-spectrum GSI treatment © 2015 Wiley Periodicals, Inc

Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.

The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα) Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer ERα signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer In this study, we demonstrate that Notch3 positively associates with ERα in both breast cancer cell lines and human breast cancer tissues We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα expression Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERα positive breast cancer patients Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy

Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α.

The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity

Aim: To investigate role of the Osteopontin (OPN) genetic polymorphisms in the susceptibility to gliomas and their prognosis Methods: </i&gt

/pdf/polymorphism-433-c-t-of-the-osteopontin-gene-is-associated-5cszstvg2m.pdf

Polymorphism -433 C>T of the Osteopontin gene is associated with the susceptibility to develop gliomas and their prognosis in a Chinese cohort.

NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients.

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Polymorphism -433 C>T of the Osteopontin gene is associated with the susceptibility to develop gliomas and their prognosis in a Chinese cohort.

NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients.