Pancreatic Cancer Stem Cells Research Articles

PPAR/PDK4 pathway is involved in the anticancer effects of cGMP in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with a high mortality rate. Current treatments for PDACs often have side effects, and drug resistance in cancer stem cells (CSCs) would be also a problem. Cyclic guanosine monophosphate (cGMP) suppresses the mitochondrial function of PDACs and inhibits their CSC properties. Metabolic regulation plays a crucial role in the maintenance of CSC phenotype, and we hypothesized that cGMP induction suppresses cancer stem cell properties in the cancer cell through energy-related signaling pathways. We demonstrated that induction of cGMP upregulated the PPARα/PDK4 pathway and suppressed CSC properties in PDAC, and patients with pancreatic cancer with high PDK4 gene expression had a better prognosis than those with low gene expression. Therefore, these mechanisms may provide new therapeutic targets for the eradication of pancreatic CSCs.

The ufmylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma

Pancreatic adenocarcinoma (PAAD) is the most malignant cancer with a high mortality rate. Despite the association of ribosomal protein L10 (RPL10) with PAAD and previous reports on RPL26 ufmylation, the relationship between RPL10 ufmylation and PAAD development remains unexplored. Here, we report the dissection of ufmylating process of RPL10 and potential roles of RPL10 ufmylation in PAAD development. The ufmylation of RPL10 was confirmed in both pancreatic patient tissues and cell lines, and specific modification sites were identified and verified. Phenotypically, RPL10 ufmylation significantly increased cell proliferation and stemness, which is principally resulted from higher expression of transcription factor KLF4. Moreover, the mutagenesis of ufmylation sites in RPL10 further demonstrated the connection of RPL10 ufmylation with cell proliferation and stemness. Collectively, this study reveals that PRL10 ufmylation plays an important role to enhance the stemness of pancreatic cancer cells for PAAD development.

Tumor Microenvironment Role in Pancreatic Cancer Stem Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a majority of patients presenting with unresectable or metastatic disease, resulting in a poor 5-year survival rate. This, in turn, is due to a highly complex tumor microenvironment and the presence of cancer stem cells, both of which induce therapy resistance and tumor relapse. Therefore, understanding and targeting the tumor microenvironment and cancer stem cells may be key strategies for designing effective PDAC therapies. In the present review, we summarized recent advances in the role of tumor microenvironment in pancreatic neoplastic progression.

Therapeutic implications of cancer stem cells in prostate cancer.

Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells (PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs; methods for isolation and enrichment of PCSCs; and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.

Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.

MicroRNAs are small, non-coding RNA molecules that regulate important cellular processes such as tumorigenesis, cell proliferation, and apoptosis. Cancer stem cells are a subset of cells that control metastasis and cell proliferation. In this study, we focus on the roles of miR-10b, miR-21 and correlate with cancer stem cells through the apoptotic pathway in different stages of prostate cancer (PCa). In total, 45 patients, each group with Benign prostatic hyperplasia (BPH), localised PCa, and metastatic PCa, were recruited. MicroRNA and gene expression were estimated through quantitative polymerase chain reaction. Flow cytometry was used to characterise prostate cancer stem cells (PCSCs), estimate reactive oxygen species (ROS), apoptosis and chemiluminescent immunoassay was used to estimate interleukin 6 (IL-6), tumour necrosis factor (TNF-α), prostate-specific antigen (PSA), and testosterone. The fold change mean expressions of miR-21, miR-10b, Cytochrome C, and B-cell lymphoma 2 (BCL-2) were significantly upregulated in localised and metastatic PCa compared with BPH. In contrast, the mean fold change expressions of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, and Second mitochondria-derived activator of caspase (SMAC) were lower in localised and metastatic PCa compared to BPH. The levels of IL-6, TNF-α, ROS, PSA and testosterone also showed a significant increase while apoptosis was decreased in both localized PCa and metastatic PCa as compared with BPH. In bioinformatics analyses, we found a similar pattern of miRNAs and gene expression in PCa databases. Our study also found a high expression of CD44+/CD24- and CD44+/CD133+ in localised and metastatic PCa compared with BPH. Our findings suggest miR-10b and miR-21 promote PCSCs and may target apoptotic genes involved in PCa pathogenesis; these miRNAs could be used as diagnosis biomarkers of PCa. In PCa pathogenesis and PCSCs regulation, the interaction between these two players is crucial and will help develop new PCa therapeutic targets.

Abstract 43: Heme Oxygenase 1 Counteracts Pro-Stemness and Pro-Invasive Effect Triggered by Communication With Bone Progenitors in Prostate Cancer Cells

Abstract Purpose: Mortality in prostate cancer (PCa) patients is mostly associated with bone metastasis and aggressive phenotypes promoted by prostate cancer stem cells (PCSCs). We have previously described that heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme catabolism with antioxidant and antiinflammatory properties, presents an antitumoral role in PCa. In this work, we assessed the role of HO-1 as a modulator of stemness and metastasis associated genes in PCa cells conditioned by bone progenitor cells. Methods: An indirect transwell co-culture system of PC3 cells, a PCa cell line, with MC3T3 cells, an osteoblast precursor cell line, was developed as an in vitro model of PCa bone metastasis. Additionally, PC3 cells were pre-treated with hemin, a pharmacological HO-1 inductor. An RNA-seq was performed to analyze the transcriptome of PC3 cells. The expression of a curated list of 87 genes associated with stemness, metastasis and the STAT3 pathway, including PCSC and classic pluripotency markers, together with a gene signature previously described by our group (ADAM15, BCL2L1, LTBR, MBNL2, SPINT1), was assessed. Results were complemented with survival data of PCa patients (TCGA-PRAD, n=565). Results: Our results showed that PC3 cells co-cultured with MC3T3 cells displayed an upregulation of PCSC markers CD44, ALDH1A3 and ALDH1L2, pluripotency markers OCT4 and SOX2, and BCL2L1 and LTBR, two genes included in our signature, compared with non-co-cultured PC3 cells. Further, when comparing co-cultured PC3 cells vs. co-cultured PC3 cells pre-treated with hemin, in the latter group the expression of 71/87 genes associated with stemness, metastasis and STAT3 pathway decreased, including CD44, ALDH1A3, ALDH1L2, OCT4, MBNL2 and ADAM15. Moreover, when evaluating patients’ disease progression free survival, those with high expression of OCT4 showed a lower risk of the event. Conclusion: HO-1 expression modulates stemness and metastasis related genes in PCa, promoting a more differentiated state, counteracting the pro-stemness effect of communication with bone progenitors. This further supports the antitumoral role of HO-1 in PCa pointing out to its potential as a therapeutic target for the disease. Citation Format: Ines Achinelli, Agustina Sabater, Pablo Sanchis, Nicolás Anselmino, Sofía Lage-Vickers, Gaston Pascual, Rocio Seniuk, Pamela Freiria, Javier Cotignola, Elba Vazquez, María Sol Ruiz, Geraldine Gueron, Ayelen Toro. Heme Oxygenase 1 Counteracts Pro-Stemness and Pro-Invasive Effect Triggered by Communication With Bone Progenitors in Prostate Cancer Cells [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 43.

CD133-Targeted Hybrid Nanovesicles for Fluorescent/Ultrasonic Imaging-Guided HIFU Pancreatic Cancer Therapy.

Pancreatic cancer is regarded as one of the most lethal types of tumor in the world, and optional way to treat the tumor are urgently needed. Cancer stem cells (CSCs) play a key role in the occurrence and development of pancreatic tumors. CD133 is a specific antigen for targeting the pancreatic CSCs subpopulation. Previous studies have shown that CSC-targeted therapy is effective in inhibiting tumorigenesis and transmission. However, CD133 targeted therapy combined with HIFU for pancreatic cancer is absent. To improve therapeutic efficiency and minimize side effects, we carry a potent combination of CSCs antibody with synergist by an effective and visualized delivery nanocarrier to pancreatic cancer. Multifunctional CD133-targeted nanovesicles (CD133-grafted Cy5.5/PFOB@P-HVs) with encapsulated perfluorooctyl bromide (PFOB) in a 3-mercaptopropyltrimethoxysilane (MPTMS) shell modified with poly ethylene glycol (PEG) and superficially modified with CD133 and Cy 5.5 were constructed following the prescribed order. The nanovesicles were characterized for the biological and chemical characteristics feature. We explored the specific targeting capacity in vitro and the therapeutic effect in vivo. The in vitro targeting experiment and in vivo FL and ultrasonic experiments showed the aggregation of CD133-grafted Cy5.5/PFOB@P-HVs around CSCs. In vivo FL imaging experiments demonstrated that the nanovesicles assemble for the highest concentration in the tumor at 24 h after administration. Under HIFU irradiation, the synergistic efficacy of the combination of the CD133-targeting carrier and HIFU for tumor treatment was obvious. CD133-grafted Cy5.5/PFOB@P-HVs combined with HIFU irradiation could enhance the tumor treatment effect not only by improving the delivery of nanovesicles but also by enhancing the HIFU thermal and mechanical effects in the tumor microenvironment, which is a highly effective targeted therapy for treating pancreatic cancer.

Cancer stem cell in prostate cancer progression, metastasis and therapy resistance

Prostate cancer (PCa) is the most diagnosed malignancy in the men worldwide. Cancer stem cells (CSCs) are the sub-population of cells present in the tumor which possess unique properties of self-renewal and multilineage differentiation thus thought to be major cause of therapy resistance, disease relapse, and mortality in several malignancies including PCa. CSCs have also been shown positive for the common stem cells markers such as ALDH EZH2, OCT4, SOX2, c-MYC, Nanog etc. Therefore, isolation and characterization of CSCs specific markers which may discriminate CSCs and normal stem cells are critical to selectively eliminate CSCs. Rapid advances in the field offers a theoretical explanation for many of the enduring uncertainties encompassing the etiology and an optimism for the identification of new stem-cell targets, development of reliable and efficient therapies in the future. The emerging reports have also provided unprecedented insights into CSCs plasticity, quiescence, renewal, and therapeutic response. In this review, we discuss the identification of PCa stem cells, their unique properties, stemness-driving pathways, new diagnostics, and therapeutic interventions.

The Molecular Biology of Prostate Cancer Stem Cells: From the Past to the Future.

Prostate cancer (PCa) continues to rank as the second leading cause of cancer-related mortality in western countries, despite the golden treatment using androgen deprivation therapy (ADT) or anti-androgen therapy. With decades of research, scientists have gradually realized that the existence of prostate cancer stem cells (PCSCs) successfully explains tumor recurrence, metastasis and therapeutic failure of PCa. Theoretically, eradication of this small population may improve the efficacy of current therapeutic approaches and prolong PCa survival. However, several characteristics of PCSCs make their diminishment extremely challenging: inherent resistance to anti-androgen and chemotherapy treatment, over-activation of the survival pathway, adaptation to tumor micro-environments, escape from immune attack and being easier to metastasize. For this end, a better understanding of PCSC biology at the molecular level will definitely inspire us to develop PCSC targeted approaches. In this review, we comprehensively summarize signaling pathways responsible for homeostatic regulation of PCSCs and discuss how to eliminate these fractional cells in clinical practice. Overall, this study deeply pinpoints PCSC biology at the molecular level and provides us some research perspectives.

Identification and Clinical Significance of Pancreatic Cancer Stem Cells and Their Chemotherapeutic Drug Resistance.

Pancreatic cancer ranks in the 10th-11th position among cancers affecting men in Taiwan, besides being a rather difficult-to-treat disease. The overall 5-year survival rate of pancreatic cancer is only 5-10%, while that of resectable pancreatic cancer is still approximately 15-20%. Cancer stem cells possess intrinsic detoxifying mechanisms that allow them to survive against conventional therapy by developing multidrug resistance. This study was conducted to investigate how to overcome chemoresistance and its mechanisms in pancreatic cancer stem cells (CSCs) using gemcitabine-resistant pancreatic cancer cell lines. Pancreatic CSCs were identified from human pancreatic cancer lines. To determine whether CSCs possess a chemoresistant phenotype, the sensitivity of unselected tumor cells, sorted CSCs, and tumor spheroid cells to fluorouracil (5-FU), gemcitabine (GEM), and cisplatin was analyzed under stem cell conditions or differentiating conditions. Although the mechanisms underlying multidrug resistance in CSCs are poorly understood, ABC transporters such as ABCG2, ABCB1, and ABCC1 are believed to be responsible. Therefore, we measured the mRNA expression levels of ABCG2, ABCB1, and ABCC1 by real-time RT-PCR. Our results showed that no significant differences were found in the effects of different concentrations of gemcitabine on CSCs CD44+/EpCAM+ of various PDAC cell line cultures (BxPC-3, Capan-1, and PANC-1). There was also no difference between CSCs and non-CSCs. Gemcitabine-resistant cells exhibited distinct morphological changes, including a spindle-shaped morphology, the appearance of pseudopodia, and reduced adhesion characteristics of transformed fibroblasts. These cells were found to be more invasive and migratory, and showed increased vimentin expression and decreased E-cadherin expression. Immunofluorescence and immunoblotting experiments demonstrated increased nuclear localization of total β-catenin. These alterations are hallmarks of epithelial-to-mesenchymal transition (EMT). Resistant cells showed activation of the receptor protein tyrosine kinase c-Met and increased expression of the stem cell marker cluster of differentiation (CD) 24, CD44, and epithelial specific antigen (ESA). We concluded that the expression of the ABCG2 transporter protein was significantly higher in CD44+ and EpCAM+ CSCs of PDAC cell lines. Cancer stem-like cells exhibited chemoresistance. Gemcitabine-resistant pancreatic tumor cells were associated with EMT, a more aggressive and invasive phenotype of numerous solid tumors. Increased phosphorylation of c-Met may also be related to chemoresistance, and EMT and could be used as an attractive adjunctive chemotherapeutic target in pancreatic cancer.

Abstract 4779: MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells

Abstract Mitochondrially-generated reactive oxygen species (mROS) have been shown to induce acinar-to-ductal metaplasia (ADM). ADM, in presence of an oncogenic KRAS mutation, is an initiating step for progression to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic ductal adenocarcinoma (PDA). Here, we utilize primary murine cells as well as the p48Cre;LSL-KrasG12D (KC) mouse model to explore the use of the mitochondria-targeted mimetic of manganese superoxide dismutase MitoQ for targeting PDA initiation and progression. Previously published data by our laboratory has shown that treatment with MitoQ decreases the abundance of pancreatic low-grade lesions in KC mice. However, we here demonstrate that superoxide depletion by MitoQ at the same time increases formation of DCLK1+ cancer stem cells in such lesions. We here evaluate if the detoxification of mitochondrial superoxide results in a build-up of hydrogen peroxide, which is a major driver of the DCLK1+ cell type. We determine how altered expression of ROS detoxifying enzymes in different cell types contribute to PDA stem cell formation and PDA development. Eventually we test if the increase in DCLK1+ cancer stem cells can contribute to changes in the microenvironment and accelerated progression of abnormal tissue. Citation Format: Jeffrey Mario Perera, Alicia K. Fleming Martinez, Peter Storz. MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4779.

Abstract 5048: Combatting pancreatic cancer stem cells by novel titanium peroxides nanoparticles combined with X-ray radiation

Abstract Background: Radiotherapy is widely used as the main treatment for multiple malignancies. However, several types of cancers, including pancreatic cancer, show resistance to radiation therapy. The presence of cancer stem cells (CSCs) are the major cause of radiation resistance in pancreatic cancer. Whereas, titanium peroxides nanoparticles (TiOxNPs) which are a modified form of titanium oxide nanoparticles promote enhanced remarkable efficacy of radiation therapy. Therefore, we examined the efficacy of TiOxNPs as radiosensitizers to eradicate pancreatic cancer stem cells. Methods and materials: In vitro, Sphere-forming assay, survival assay, migration, and invasion assay were evaluated after using TiOxNPs prior to radiation exposure to pancreatic cancer cell line. In vivo, tumor-bearing nude mice were injected by TiOxNPs either intratumoral or intravenous one hour prior to radiation treatment, and the tumor volume, body weight, and mice survival was calculated. In addition, proteins-related stemness were measured in vitro and in vivo to evaluate the usage of TiOxNPs as radiosensitizers to pancreatic CSCs. Moreover, we planned to evaluate the mechanism beyond the efficacy of TiOxNPs as radiosensitizers to CSCs by detecting reactive oxygen species (ROS) production, mitochondrial function, and the phosphorylation of some signaling proteins. We found that TiOxNPs combined with ionizing radiation showed anti-cancer effects on radioresistant CSCs both in vitro and in vivo. Results: In vitro, a marked reduction in growth was detected after exposing the TiOxNPs-treated cells to radiation therapy, specifically with a 5Gy dose compared with 2Gy dose. TiOxNPs exhibited a synergistic effect with radiation on pancreatic CSC-enriched spheres by downregulating self-renewal regulatory factors and CSC surface markers. In vivo, we first established an aggressive xenograft by injecting MIA PaCa-2 sphere cells into the flank region of BALB/c nude mice, and found that animals treated with combined TiOxNPs and irradiation showed a dramatic reduction in tumor volume and weight compared to the untreated group. Moreover, combined treatment suppressed epithelial-mesenchymal transition, migration, and invasion properties in primary and aggressive pancreatic cancer cells by reducing the expression of proteins relevant to these processes. Radiosensitizing TiOxNPs suppressed pancreatic xenograft outgrowth after primary or dissociating sphere MIA PaCa-2 cell implantation. It is assumed that synergy is created by inactivating the AKT signaling pathway and producing unbearable amounts of ROS. Conclusion: Our findings showed that using TiOxNPs in combination with radiation might be a favorable therapeutic approach to eradicate pancreatic CSCs. Citation Format: Mohammed Salah, Hiroki Kawaguchi, Hiroaki Akasaka, Yasuyuki Shimizu, Kenta Morita, Yuya Nishimura, Hikaru Kubota, Tomomi Sogawa, Naritoshi Mukumoto, Chiaki Ogino, Ryohei Sasaki. Combatting pancreatic cancer stem cells by novel titanium peroxides nanoparticles combined with X-ray radiation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5048.

Identification of a peptide ligand for human ALDH3A1 through peptide phage display: Prediction and characterization of protein interaction sites and inhibition of ALDH3A1 enzymatic activity.

Aldehyde dehydrogenase 3A1 (ALDH3A1) by oxidizing medium chain aldehydes to their corresponding carboxylic acids, is involved in the detoxification of toxic byproducts and is considered to play an important role in antioxidant cellular defense. ALDH3A1 has been implicated in various other functions such as cell proliferation, cell cycle regulation, and DNA damage response. Recently, it has been identified as a putative biomarker of prostate, gastric, and lung cancer stem cell phenotype. Although ALDH3A1 has multifaceted functions in both normal and cancer homeostasis, its modes of action are currently unknown. To this end, we utilized a random 12-mer peptide phage display library to identify efficiently human ALDH3A1-interacting peptides. One prevailing peptide (P1) was systematically demonstrated to interact with the protein of interest, which was further validated in vitro by peptide ELISA. Bioinformatic analysis indicated two putative P1 binding sites on the protein surface implying biomedical potential and potent inhibitory activity of the P1 peptide on hALDH3A1 activity was demonstrated by enzymatic studies. Furthermore, in search of potential hALDH3A1 interacting players, a BLASTp search demonstrated that no protein in the database includes the full-length amino acid sequence of P1, but identified a list of proteins containing parts of the P1 sequence, which may prove potential hALDH3A1 interacting partners. Among them, Protein Kinase C Binding Protein 1 and General Transcription Factor II-I are candidates of high interest due to their cellular localization and function. To conclude, this study identifies a novel peptide with potential biomedical applications and further suggests a list of protein candidates be explored as possible hALDH3A1-interacting partners in future studies.

Adipocytes reprogram prostate cancer stem cell machinery.

It is now well-established that an obese condition correlates with a higher risk of prostate cancer (PCa). A crosstalk between adipose tissue and PCa has been observed but is still poorly characterized. Herein, we demonstrated that 3T3-L1 adipocyte conditioned media (CM) could endow PC3 and DU145 PCa cells with stemness properties, by stimulating their sphere formation ability and promoting CD133 and CD44 expression. Moreover, after exposure to adipocyte CM both PCa cell lines underwent partial epithelial-to-mesenchymal transition (EMT), with E-/N-cadherin switch and Snail upregulation. Specifically, these changes in PC3 and DU145 cell phenotype were accompanied by increased tumor clonogenic activity and survival, as well as by enhanced invasion, anoikis resistance and matrix metalloproteinase (MMP) production. Finally, adipocyte CM-treated PCa cells exhibited reduced responsiveness to both docetaxel and cabazitaxel, demonstrating greater chemoresistance. Overall, these data indicate that adipose tissue can effectively contribute to PCa aggressiveness by reprogramming the cancer stem cell (CSC) machinery. Adipocytes endow prostate cancer cells with stem-like properties and mesenchymal traits, increasing their tumorigenicity, invasion and chemoresistance.

State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer.

The development of new therapeutic strategies is on the increase for prostate cancer stem cells, owing to current standardized therapies for prostate cancer, including chemotherapy, androgen deprivation therapy (ADT), radiotherapy, and surgery, often failing because of tumor relapse ability. Ultimately, tumor relapse develops into advanced castration-resistant prostate cancer (CRPC), which becomes an irreversible and systemic disease. Hence, early identification of the intracellular components and molecular networks that promote prostate cancer is crucial for disease management and therapeutic intervention. One of the potential therapeutic methods for aggressive prostate cancer is to target prostate cancer stem cells (PCSCs), which appear to be a primary focal point of cancer metastasis and recurrence and are resistant to standardized therapies. PCSCs have also been documented to play a major role in regulating tumorigenesis, sphere formation, and the metastasis ability of prostate cancer with their stemness features. Therefore, the current review highlights the origin and identification of PCSCs and their role in anti-androgen resistance, as well as stemness-related signaling pathways. In addition, the review focuses on the current advanced therapeutic strategies for targeting PCSCs that are helping to prevent prostate cancer initiation and progression, such as microRNAs (miRNAs), nanotechnology, chemotherapy, immunotherapy, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing system, and photothermal ablation (PTA) therapy.

SFRP1 induces a stem cell phenotype in prostate cancer cells.

Prostate cancer (PCa) ranks second in incidence and sixth in deaths globally. The treatment of patients with castration-resistant prostate cancer (CRPC) continues to be a significant clinical problem. Emerging evidence suggests that prostate cancer progression toward castration resistance is associated with paracrine signals from the stroma. SFRP1 is one of the extracellular proteins that modulate the WNT pathway, and it has been identified as a mediator of stromal epithelium communication. The WNT pathway is involved in processes such as cell proliferation, differentiation, cell anchoring, apoptosis, and cell cycle regulation as well as the regulation of stem cell populations in the prostatic epithelium. In the present study, we explored the role of exogenous SFRP1 on the stem cell phenotype in prostate cancer. The results reveal that cancer stem cell markers are significantly increased by exogenous SFRP1 treatments, as well as the downstream target genes of the Wnt/-catenin pathway. The pluripotent transcription factors SOX2, NANOG, and OCT4 were also up-regulated. Furthermore, SFRP1 promoted prostate cancer stem cell (PCSC) properties in vitro, including tumorsphere formation, migration, bicalutamide resistance, and decreased apoptosis. Taken together, our results indicate that SFRP1 participates in the paracrine signaling of epithelial cells, influencing them and positively regulating the stem cell phenotype through deregulation of the WNT/β-catenin pathway, which could contribute to disease progression and therapeutic failure. This research increases our molecular understanding of how CRPC progresses, which could help us find new ways to diagnose and treat the disease.

Pharmacological inhibition of the SKP2/p300 signaling axis restricts castration-resistant prostate cancer

SKP2, an F-box protein of the SCF type of the E3 ubiquitin ligase complex, plays an important function in driving tumorigenesis through the destruction of numerous tumor-suppressive proteins. Besides its critical role in cell cycle regulation, proto-oncogenic functions of SKP2 have also been shown in a cell cycle regulation-independent manner. Therefore, uncovering novel physiological upstream regulators of SKP2 signaling pathways would be essential to retard aggressive malignancies. Here, we report that elevation of SKP2 and EP300 transcriptomic expression is a hallmark of castration-resistant prostate cancer. We also found that SKP2 acetylation is likely a critical driven event in castration-resistant prostate cancer cells. Mechanistically, SKP2-acetylation is mediated by the p300 acetyltransferase enzyme for post-translational modification (PTM) event that is induced upon stimulation with dihydrotestosterone (DHT) in prostate cancer cells. Moreover, ectopic expression of acetylation-mimetic K68/71Q mutant of SKP2 in LNCaP cells could confer resistance to androgen withdrawal-induced growth arrest and promotes prostate cancer stem cell (CSC)-like traits including survival, proliferation, stemness formation, lactate production, migration, and invasion. Furthermore, inhibition of p300-mediated SKP2 acetylation or SKP2-mediated p27-degradation by pharmacological inhibition of p300 or SKP2 could attenuate epithelial-mesenchymal transition (EMT) and the proto-oncogenic activities of the SKP2/p300 and androgen receptor (AR) signaling pathways. Therefore, our study identifies the SKP2/p300 axis as a possible molecular mechanism driving castration-resistant prostate cancers, which provides pharmaceutical insight into inactivation of the SKP2/p300 axis for restriction of CSC-like properties, thereby benefiting clinical diagnosis and cancer therapy.

Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1α/Notch1 signaling pathway.

The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated. Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated. In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa. In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.

The Role of Signaling Pathways in Pancreatic Cancer Targeted Therapy.

Signaling pathways play significant roles in the occurrence, development, and treatment of pancreatic cancer (PC). The main treatment options are surgery, chemotherapy, radiotherapy, arterial infusion chemotherapy in interventional therapy, and immunotherapy. Many studies have shown that signaling pathways perform a function in the occurrence and development of PC, for instance, phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor-κB, Ras, interleukin (IL)-17B/IL-17RB, Wnt, and hepatocyte growth factor/c-MET, which play roles in the proliferation, metastasis, invasion, inhibition of apoptosis, promotion of angiogenesis, and drug resistance of PC. Interaction of signaling pathways has an impact on the biological behavior of PC; for example, activation of the neurotensin/NTSR1 pathway, which can activate mitogen-activated protein kinase, nuclear factor-κB, and other pathways related to PC stem cells, play an important role in PC, and an increase in their number is associated with the Wnt/β-catenin and PI3K pathways. Chemotherapy is the main method for the treatment of PC, but drug resistance limits its use. In addition, abnormal activation of IL-17B/IL-17RB signaling pathway is associated with drug resistance. This article discusses the signaling pathways that play different roles in the occurrence and development of PC, as well as current research on signaling pathways in PC treatment.

Expression of the Low-density Lipoprotein Receptor (LDLR) Gene Family in CD133+/CD44+ Prostate Cancer Stem Cells

Aim: The low-density lipoprotein receptor gene (LDLR) family plays a fundamental role in many malignancies and may have a putative cancer-boosting function. In our study, we have attempted to comparatively investigate the differential gene expressions of LDLR family in normal prostate epithelial cell line (RWPE-1), prostate cancer cell line (DU145 cell line), prostate cancer stem cells (DU145 CSCs) and non-CSCs (DU145 non-CSCs, bulk population). 
 Materials and Methods: Cancer stem cells in DU-145 prostate cancer cell line were isolated by flow cytometry according to CD133 and CD44 cell surface properties. Whole transcriptome sequencing data was comprehensively analyzed for each group. The protein-protein interaction network was determined using the STRING protein database.
 Results: Our data showed that the expression levels of LRP1, LRP3, LRP8 and LRP11 were increased in the DU145 CSCs relative to the normal prostate epithelial cell line. 
 Conclusion: Overall, our data suggest that the LRP functions and/or the expression in prostate cancer may ultimately change the invasive phenotype of the CSCs.