Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Yasuda, Kazuyo; Torigoe, Toshihiko; Mariya, Tasuku; Asano, Takuya; Kuroda, Takafumi; Matsuzaki, Junichi; Ikeda, Kimiyuki; Yamauchi, M.; Emori, Makoto; Asanuma, Hiroko; Hasegawa, Tadashi; Saito, Tsuyoshi; Hirohashi, Yoshihiko; Sato, Noriyuki

doi:10.1038/labinvest.2014.122

Cited by 54 publications

(49 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They then activate downstream signal molecules during epithelial-to-mesenchymal transition of tumor cells (40). Some researchers suggested that the expression of FGF4 and FGFR2 in ovarian cancer stemlike cells/cancer-initiating cells promoted their tumor initiation capacity (41). Our mass spectrometry results show that PIWIL4 promotes the TGF-␤ and FGF signaling pathways in the breast cancer cell line MDA-MB-231, which links PIWIL4 function to these important signaling pathways.…”

Section: Discussionsupporting

confidence: 52%

The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer

Wang

Liu

Shi

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

P-element-induced wimpy testis (PIWI) proteins bind to PIWI-interacting RNAs and play key roles in the biogenesis and functions of PIWI-interacting RNAs. It has been reported that PIWI proteins are essential for stem cell self-renewal and germline development in diverse organisms and that they are ectopically expressed in multiple forms of cancer. However, the role of PIWI in cancer remains elusive. Here we report that one of the four PIWI proteins in humans, PIWIL4, is highly expressed in both breast cancer tissues and the cytoplasm of MDA-MB-231 cells derived from breast cancer. Reducing PIWIL4 expression drastically impairs the migration ability of MDA-MB-231 cells, significantly increases their apoptosis, and mildly affects their proliferation. Our transcriptome and proteome analysis reveal that these functions are at least partially achieved via the PIWIL4 regulation of TGF-␤ and FGF signaling pathways and MHC class II proteins. These findings suggest that PIWIL4 may serve as a potential therapeutic target for breast cancer.PIWI 5 proteins represent a subfamily of the Argonaute (Ago) protein family and are highly conserved among eukaryotes and archaea. PIWI proteins bind to a class of non-coding small RNAs called PIWI-interacting RNAs (piRNAs) (1-4). The PIWI-piRNA complex regulates gene expression at epigenetic and posttranscriptional levels (5-8). PIWI proteins and piRNAs are mostly expressed in the germ line, where PIWI proteins have been demonstrated to be essential for germ line development, stem cell self-renewal, and gametogenesis in diverse organisms (4, 9 -14). In addition, there is increasing evidence for somatic expression of PIWI proteins in Drosophila and mouse tissues (14 -16). Furthermore, it has been reported that PIWI proteins have aberrant and ectopic expression in a wide spectrum of cancers (17-23). For example, PIWIl2 is highly expressed in breast cancer (24). Hence, PIWI might be involved in cancer formation and/or progression.Breast cancer comprises four subtypes based on the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER2). Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and HER2 expression (25-27), represents ϳ10 -25% of all breast cancers, and is a clinical therapy hot spot because of the vulnerability of younger women to this subtype of breast cancer (28). Furthermore, TNBC patients do not benefit from targeted treatments such as endocrine therapy or trastuzumab because this subtype of cancer lacks the appropriate targets for these drugs. These challenges point to the pressing need to identify pathogenic pathways in TNBC. Recent studies have identified genetic alterations and gene expression profiles associated with subtypes of TNBC, including the implication of the PI3K/Akt/mTOR (mechanistic target of rapamycin) pathway in TNBC (29 -32). However, therapeutic blockade of this pathway with the PI3K/Akt/mechanistic target of rapamycin inhibitor has not been effective, indicating the existenc...

show abstract

Section: Discussionsupporting

confidence: 52%

The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer

Wang

Liu

Shi

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Conversely, co-overexpression of Zeb1 and Zeb2 enhanced sphere-forming ability of head and neck cancer cells [57]. FGF4 is shown to play a key role in maintaining self-renewal capacity of normal and cancer stem cells [58, 59]. FGF4 promoted self-renewal of CSC-enriched population [59].…”

Section: Discussionmentioning

confidence: 99%

“…FGF4 is shown to play a key role in maintaining self-renewal capacity of normal and cancer stem cells [58, 59]. FGF4 promoted self-renewal of CSC-enriched population [59]. …”

Section: Discussionmentioning

confidence: 99%

Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma

Lee¹,

Rigas²,

Lee³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Emerging evidence indicates that Orai1, a key calcium channel for store-operated Ca2+ entry, is associated with human cancer. However, the underlying mechanism by which Orai1 regulates cancer progression remains unknown. Here we report that intracellular level of Orai1 is increased in a stepwise manner during oral/oropharyngeal carcinogenesis and highly expressed in cancer stem-like cell (CSC)-enriched populations of human oral/oropharyngeal squamous cell carcinoma (OSCC). Ectopic Orai1 expression converted non-tumorigenic immortalized oral epithelial cells to malignant cells that showed CSC properties, e.g., self-renewal capacity, increased ALDH1HIGH cell population, increased key stemness transcription factors, and enhanced mobility. Conversely, inhibition of Orai1 suppressed tumorigenicity and CSC phenotype of OSCC, indicating that Orai1 could be an important element for tumorigenicity and stemness of OSCC. Mechanistically, Orai1 activates its major downstream effector molecule, NFATc3. Knockdown of NFATc3 in the Orai1-overexpressing oral epithelial cells abrogates the effect of Orai1 on CSC phenotype. Moreover, antagonist of NFAT signaling also decreases CSC phenotype, implying the functional importance of Orai1/NFAT axis in OSCC CSC regulation. Our study identifies Orai1 as a novel molecular determinant for OSCC progression by enhancing cancer stemness, suggesting that inhibition of Orai1 signaling may offer an effective therapeutic modality against OSCC.

show abstract

“…The stroma has also been shown to promote the acquisition of stem-like properties by cancer cells, providing a fertile niche in which primary cancer cells can grow, and metastatic cancer cells can colonize 183,184 . The early stages of colon cancer are thought to be driven by the stem cell niche: stromal fibroblasts secrete Wnt ligands that promote β-catenin-dependent signalling in colon epithelial cells, driving a cancer stem cell-like phenotype 185 .…”

Section: Stroma–cancer Interactionsmentioning

confidence: 99%

Targeting the tumour stroma to improve cancer therapy

2018

View full text Add to dashboard Cite

Cancers are not merely composed of cancer cells alone and, instead, are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistroma agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions, and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

show abstract

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Cited by 54 publications

References 34 publications

The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer

The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer

Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma

Targeting the tumour stroma to improve cancer therapy

Contact Info

Product

Resources

About