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Cancers, Volume 9, Issue 3 (March 2017) – 6 articles

Cover Story (view full-size image): The progression of prostate cancer (PC) is influenced by androgens and the androgen receptor (AR). PC develops resistance to low testosterone levels called castration-resistant PC (CRPC). Surprisingly, the AR signaling pathway are still activated by some of the AR collaborative transcription factors (TFs) in most CRPC cases. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. We summarize the AR signaling pathways in terms of collaborative TFs and focus on pyrrole-imidazole polyamides as candidate compounds for the treatment of PC. View the paper

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255 KiB

Open AccessArticle

Predictors of Posttraumatic Stress and Posttraumatic Growth in Childhood Cancer Survivors

by Veronika Koutná, Martin Jelínek, Marek Blatný and Tomáš Kepák

Cancers 2017, 9(3), 26; https://doi.org/10.3390/cancers9030026 - 16 Mar 2017

Cited by 40 | Viewed by 7393

Abstract

This longitudinal study aims to analyze predictors of posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) among gender, age, objective factors of the disease and its treatment, family environment factors and negative emotionality. The sample consisted of 97 childhood cancer survivors (50 girls and 47 boys) aged 11–25 years who were in remission 1.7 to seven years at T1 and four to 12.5 years at T2. Survivors completed a set of questionnaires including the Benefit Finding Scale for Children and the University of California at Los Angeles Posttraumatic Stress Disorder Index. Regression and correlation analyses were performed. The relation between PTSS and PTG was not proven. A higher level of PTSS (T2) was associated with higher levels of negative emotionality (T1). A higher level of PTG (T2) was connected to a higher level of warmth in parenting (T1), female gender and older age at assessment. Medical variables such as the severity of late effects and the time from treatment completion did not play a significant role in the prediction of PTSS and PTG. PTG and PTSS are more influenced by factors of parenting and emotional well-being of childhood cancer survivors than by objective medical data. Full article

(This article belongs to the Special Issue Quality of Life for Cancer Patients)

1805 KiB

Open AccessReview

Serine/Threonine Kinase 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) as a Key Regulator of Cell Migration and Cancer Dissemination

by Laura Di Blasio, Paolo A. Gagliardi, Alberto Puliafito and Luca Primo

Cancers 2017, 9(3), 25; https://doi.org/10.3390/cancers9030025 - 11 Mar 2017

Cited by 54 | Viewed by 11252

Abstract

Dissecting the cellular signaling that governs the motility of eukaryotic cells is one of the fundamental tasks of modern cell biology, not only because of the large number of physiological processes in which cell migration is crucial, but even more so because of the pathological ones, in particular tumor invasion and metastasis. Cell migration requires the coordination of at least four major processes: polarization of intracellular signaling, regulation of the actin cytoskeleton and membrane extension, focal adhesion and integrin signaling and contractile forces generation and rear retraction. Among the molecular components involved in the regulation of locomotion, the phosphatidylinositol-3-kinase (PI3K) pathway has been shown to exert fundamental role. A pivotal node of such pathway is represented by the serine/threonine kinase 3-phosphoinositide-dependent protein kinase-1 (PDPK1 or PDK1). PDK1, and the majority of its substrates, belong to the AGC family of kinases (related to cAMP-dependent protein kinase 1, cyclic Guanosine monophosphate-dependent protein kinase and protein kinase C), and control a plethora of cellular processes, downstream either to PI3K or to other pathways, such as RAS GTPase-MAPK (mitogen-activated protein kinase). Interestingly, PDK1 has been demonstrated to be crucial for the regulation of each step of cell migration, by activating several proteins such as protein kinase B/Akt (PKB/Akt), myotonic dystrophy-related CDC42-binding kinases alpha (MRCKα), Rho associated coiled-coil containing protein kinase 1 (ROCK1), phospholipase C gamma 1 (PLCγ1) and β3 integrin. Moreover, PDK1 regulates cancer cell invasion as well, thus representing a possible target to prevent cancer metastasis in human patients. The aim of this review is to summarize the various mechanisms by which PDK1 controls the cell migration process, from cell polarization to actin cytoskeleton and focal adhesion regulation, and finally, to discuss the evidence supporting a role for PDK1 in cancer cell invasion and dissemination. Full article

(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)

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785 KiB

Open AccessReview

Class (I) Phosphoinositide 3-Kinases in the Tumor Microenvironment

by David Gyori, Tamara Chessa, Phillip T. Hawkins and Len R. Stephens

Cancers 2017, 9(3), 24; https://doi.org/10.3390/cancers9030024 - 4 Mar 2017

Cited by 32 | Viewed by 8278

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a diverse family of enzymes which regulate various critical biological processes, such as cell proliferation and survival. Class (I) PI3Ks (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ) mediate the phosphorylation of the inositol ring at position D3 leading to the generation of PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 can be dephosphorylated by several phosphatases, of which the best known is the 3-phosphatase PTEN (phosphatase and tensin homolog). The Class (I) PI3K pathway is frequently disrupted in human cancers where mutations are associated with increased PI3K-activity or loss of PTEN functionality within the tumor cells. However, the role of PI3Ks in the tumor stroma is less well understood. Recent evidence suggests that the white blood cell-selective PI3Kγ and PI3Kδ isoforms have an important role in regulating the immune-suppressive, tumor-associated myeloid cell and regulatory T cell subsets, respectively, and as a consequence are also critical for solid tumor growth. Moreover, PI3Kα is implicated in the direct regulation of tumor angiogenesis, and dysregulation of the PI3K pathway in stromal fibroblasts can also contribute to cancer progression. Therefore, pharmacological inhibition of the Class (I) PI3K family in the tumor microenvironment can be a highly attractive anti-cancer strategy and isoform-selective PI3K inhibitors may act as potent cancer immunotherapeutic and anti-angiogenic agents. Full article

(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)

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2779 KiB

Open AccessReview

Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA)

by Yutaka Yonemura, Yoshio Endo, Emel Canbay, Yang Liu, Haruaki Ishibashi, Akiyoshi Mizumoto, Masamitu Hirano, Yuuki Imazato, Nobuyuki Takao, Masumi Ichinose, Kousuke Noguchi, Yan Li, Satoshi Wakama, Kazuhiro Yamada, Koutarou Hatano, Hiroshi Shintani, Hiroyuki Yoshitake and Shun-ichiro Ogura

Cancers 2017, 9(3), 23; https://doi.org/10.3390/cancers9030023 - 1 Mar 2017

Cited by 13 | Viewed by 7359

Abstract

In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM. Full article

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Open AccessReview

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

by Daisuke Obinata, Kenichi Takayama, Satoru Takahashi and Satoshi Inoue

Cancers 2017, 9(3), 22; https://doi.org/10.3390/cancers9030022 - 28 Feb 2017

Cited by 34 | Viewed by 8832

Abstract

Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer. Full article

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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Open AccessReview

AR Signaling in Breast Cancer

by Bilal Rahim and Ruth O’Regan

Cancers 2017, 9(3), 21; https://doi.org/10.3390/cancers9030021 - 24 Feb 2017

Cited by 90 | Viewed by 12650

Abstract

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies. Full article

(This article belongs to the Special Issue AR Signaling in Human Malignancies: Prostate Cancer and Beyond)

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