Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-β, hedgehog (Hh), Notch, Wnt/β-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.

/pdf/mechanistic-pathways-of-malignancy-in-breast-cancer-stem-37dskt6nix.pdf

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells.

A newly synthesized isoquinolinesulfonamide, H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide), was shown to have a potent and selective inhibitory action against cyclic AMP-dependent protein kinase (protein kinase A), with an inhibition constant of 0.048 +/- 0.008 microM. H-89 exhibited weak inhibitory action against other kinases and Ki values of the compound for these kinases, including cGMP-dependent protein kinase (protein kinase G), Ca2+/phospholipid-dependent protein kinase (protein kinase C), casein kinase I and II, myosin light chain kinase, and Ca2+/calmodulin-dependent protein kinase II were 0.48 +/- 0.13, 31.7 +/- 15.9, 38.3 +/- 6.0, 136.7 +/- 17.0, 28.3 +/- 17.5, and 29.7 +/- 8.1 microM, respectively. Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP. To examine the role of protein kinase A in neurite outgrowth of PC12 cells, H-89 was applied along with nerve growth factor (NGF), forskolin, or dibutyryl cAMP. Pretreatment with H-89 led to a dose-dependent inhibition of the forskolin-induced protein phosphorylation, with no decrease in intracellular cyclic AMP levels in PC12D cells, and the NGF-induced protein phosphorylation was not not inhibited. H-89 also significantly inhibited the forskolin-induced neurite outgrowth from PC12D cells. This inhibition also occurred when H-89 was added before the addition of dibutyryl cAMP. Pretreatment of PC12D cells with H-89 (30 microM) inhibited significantly cAMP-dependent histone IIb phosphorylation activity in cell lysates but did not affect other protein phosphorylation activity such as cGMP-dependent histone IIb phosphorylation activity, Ca2+/phospholipid-dependent histone IIIs phosphorylation activity, Ca2+/calmodulin-dependent myosin light chain phosphorylation activity, and alpha-casein phosphorylation activity. However, this protein kinase A inhibitor did not inhibit the NGF-induced neurite outgrowth from PC12D cells. Thus, the forskolin- and dibutyryl cAMP-induced neurite outgrowth is apparently mediated by protein kinase A while the NGF-induced neurite outgrowth is mediated by a protein kinase A-independent pathway.

Inhibition of Forskolin-induced Neurite Outgrowth and Protein Phosphorylation by a Newly Synthesized Selective Inhibitor of Cyclic AMP-dependent Protein Kinase, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfinamide (H-89), of PC12D Pheochromocytoma

Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal–fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO’s commitment to eliminate HBV and viral hepatitis by 2030.

Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma.

Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear. Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism. Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3β signaling and facilitate β-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting β-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo. Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.

CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis.

Abstract Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies. 

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

Considerable evidence suggests that as breast cancer progresses, genetic and epigenetic mechanisms contribute to the emergence of self-renewing cells (CSC), which may also arise as a consequence of metastasis. Although the molecular pathways that trigger stemness and metastasis are known, key molecular and mechanistic gaps in our understanding of these processes remain unclear. Here, we first screened the inflammation-associated stemness gene phosphodiesterase 3A (PDE3A) using a medium-throughput siRNA library, which was overexpressed in breast tumors and significantly correlated with clinical progression. PDE3A induced the inflammatory nuclear factor NFκB signaling pathway by suppressing cAMP/PKA, which promotes the expression of the stem cell marker OCT4. In addition, PDE3A also promoted the translocation of CCDC88A from the cytoplasm to nuclei, thereby boosting the invasion-metastasis cascade in breast cancer. Most importantly, the PDE3A-selective inhibitor cilostazol dramatically suppressed breast tumor growth and reduced metastasis to the lungs in xenograft breast cancer models, with minimum toxicity. Taken together, we show that PDE3A could predispose patients with breast cancer to metastases by acting as a mediator of cancer stemness. PDE3A is a potential therapeutic target for advanced breast cancer.

/pdf/phosphodiesterase-3a-represents-a-therapeutic-target-that-34ou3u0ncv.pdf

Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell-like Property and Metastasis in Breast Cancer.

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Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell-like Property and Metastasis in Breast Cancer.