CXCR4 Expression in Prostate Cancer Progenitor Cells

Cho

et al. 2014

Intl Journal of Cancer

Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related deaths in males in the United States. 1 Although androgen depletion therapy is highly effective in suppressing PC growth, persistent androgen ablation often results in the development of metastatic castration resistant prostate cancer (CRPC). 2 Currently, patients with metastatic CRPC are treated with taxane-based chemotherapeutic drugs. However, the treatment only serves as a palliative, and distant metastasis is the main cause of PC-related death. 3 Therefore, the identification of novel therapeutic targets in metastatic CRPC is the most urgent clinical requirement that remains unmet.Tumors contain a reservoir of cancer stem cells (CSCs) that are responsible for tumor initiation, progression, metastasis and therapeutic resistance. 4 Since emerging evidence suggests that PC CSCs represent the "bad seeds" of tumor, the molecular mechanisms that maintain PC CSCs could potentially serve as therapeutic targets for metastatic CRPC. 5,6 Although aldehyde dehydrogenase (ALDH) activity 7 and expression of CD44 8 and Bmi-1 9 have been suggested as specific PC CSC markers, using these markers as therapeutic targets is challenging because the molecules lack specific functional and/or enzymatic activities.Tumor progression locus 2 [Tpl2/MAP3 kinase 8 (MAP3K8)], a serine/threonine protein kinase, has been suggested to enhance tumor growth and metastatic progression in distinct types of human cancers. 10-12 Previously, we

Section: Discussionmentioning

confidence: 64%

Tpl2 induces castration resistant prostate cancer progression and metastasis

Cho

et al. 2014

Intl Journal of Cancer

“…growing number of people are diagnosed with colon cancer [82] . Suicide gene systems including HSV-TK have been used to treat gastrointestinal cancers.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…There are numerous studies on HSV-TK suicide genes, 5-FC+GCV prodrug therapy, NTR/CB1954, and nitro reductase system on prostate cancer. Several biomarkers including prostatespecific antigen (PSA), prostate-specific membrane antigen (PSMA), androgen, C-X-C chemokine receptor type 4 (CXCR4), and epithelial cell adhesion molecule (EpCAM) have been identified for prostate cancer [82][83][84] . Consequently, promoters of the aforementioned genes are incorporated into the constructs of cancer suicide genes, which are expressed in prostate cancer cells [61,65] .…”

Section: Clinical Applicationsmentioning

confidence: 99%

The war against cancer: Suicide gene therapy

2016

Abstract:The National Cancer Institute and the American Cancer Society announced that 1.6 million new cancer cases are projected to occur in the USA in 2016. One of the most innovative approaches against cancer is suicide gene therapy, in which suicide-inducing transgenes are introduced into cancer cells. When cancer treatments target the total elimination of tumor cells, there will be no side effects for normal cells. Cancer tissues are targeted through various targeted transport methods, followed by tissue-specific enzymes converting a systemically suitable prodrug into an active drug in the tumor. Suicidal genes are delivered by transporters, such as viral and non-viral vectors, into cancer cells. Suicide gene therapeutic strategies currently pursued are herpes simplex virus thymidine kinase gene with prodrug ganciclovir, cytosine deaminase gene, carboxyl esterase/irinotecan, varicella zoster virus thymidine kinase/6-methoxypurine arabinonucleoside, nitroreductase Nfsb/5-(aziridin-1-yl)-2,4-dinitrobenzamide, carboxypeptidase G2/4-[(2-chloroethyl) (2-mesyloxyethyl)amino] benzoyl-L-glutamic acid, cytochrome p450-isofosfamide, and cytochrome p450-cyclophosphamide. The goal of this review is to summarize the different suicide gene systems and gene delivery vectors addressed to cancer cells, with a particular emphasis on recently developed systems. Finally, we briefly describe the advantageous clinical applications and potential side effects of suicide gene therapy.

“…Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death [1] . Many Americans are affected by pancreatic cancer [1] and a growing number of people are diagnosed with colon cancer [82] . Suicide gene systems including HSV-TK have been used to treat gastrointestinal cancers.…”

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

AMOR Vol. 2, Issue 3, 2016

Office¹

2016

Adv Mod Oncol Res

astric cancer is a significant cause of cancer-related mortality and morbidity. In terms of disease etiology, it ranks as the fourth and fifth most common contributor of male and female cancer-related death, respectively [1] . A marked geographical variability has been observed for gastric cancer incidence, with the majority of cases reported in Eastern Europe, South America, and Asia [2] . This has been ascribed to environmental (e.g., H. pylori infection), dietary, as well as genetic factors [3] . H. pylori is considered as a definite carcinogen by the International Agency for Research on Cancer, and intestinal metaplasia has been suggested as the intermediate event in the development of H. pylori-related gastric cancer [4] . However, the molecular mechanism of this event needs to be further elucidated. In this issue of AMOR, a report from Ukraine's Vinnitsa National Pigorov Memorial Medical University by Sergii Vernygorodskyi attempts to improve our current understanding of the molecular mechanism associated with H. pylori-related gastric carcinogenesis [5] . The investigator found that the activation of CDX2, along with the simultaneous inactivation and a decreased number of genes (e.g., SHH, SOX2, and RUNX3) responsible for gastric differentiation, is a probable cause that leads to the appearance of intestinal metaplasia.Therefore, this study serves as an important catalyst to promote further research on the molecular mechanism and programming of gastric cancer cells, in hopes of gaining new knowledge in the prevention and treatment of gastric cancer. Conflict of interestThe author declares no potential conflict of interest with respect to the research, authorship, and/or publication of this article. References 1.Jemal scientist recounted the story of his dangerous experiment that led to him being awarded a Nobel Prize in 2005: "I had a patient with gastritis. I got the bacteria from his stomach and cultured them...I swizzled the organisms around in a cloudy broth and drank it the next morning."He added, "My stomach gurgled, and after five days...I'd run in the bathroom and vomit. After 10 days I had an endoscopy that showed the bacteria were everywhere. There was all this inflammation, and gastritis had developed."The Australian physician Dr. Barry Marshall, dubbed "the guinea-pig doctor" after the exploit, drank the germs as a last resort in his attempt to prove that the Helicobacter pylori (or "H. pylori") bacteria caused stomach ulcers, which could lead to cancer if left untreated.Ulcer's cure is relatively simple -antibiotics -but Dr. Marshall asserted that during his days as a physician, a majority of the medical elites believed that ulcers were caused by stress and dismissed unexplained conditions as "all in the head".As he was unable conduct his study on mice (H. pylori only affects primates), he ran the experiment on the only human patient who would consent to such a procedure: himself.More than a decade after the brave doctor infected himself and remedied his self-induced illness with ant...