Publications by authors named "Jill Squires"

10 Publications

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Making a Tissue Microarray.

Methods Mol Biol 2019 ;1897:313-323

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Tissue microarray (TMA) is a widely used, high-throughput, cost-effective, and tissue and reagent-conserving method of performing molecular analysis. Multiple donor tissue cores are procured and transferred into a recipient TMA block for simultaneous differential and comparative molecular profiling under theoretically identical performance conditions. Described herein is a discussion of the theory behind the TMA, an overview of the concepts and principles of TMA design and construction, a brief summary of its advantages and disadvantages, and a sample protocol of TMA construction.
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http://dx.doi.org/10.1007/978-1-4939-8935-5_27DOI Listing
June 2019

UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression.

BMC Cancer 2017 Jul 3;17(1):463. Epub 2017 Jul 3.

Cedars-Sinai Health System, Center for Integrated Research on Cancer and Lifestyle, Cancer Genetics and Prevention Program, Surgery, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.

Background: Uridine 5'-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.

Methods: We determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein's percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR.

Results: The median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).

Conclusions: Our findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases.
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http://dx.doi.org/10.1186/s12885-017-3463-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496250PMC
July 2017

Potential therapeutic effect of epigenetic therapy on treatment-induced neuroendocrine prostate cancer.

Asian J Androl 2017 Nov-Dec;19(6):686-693

Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California, USA.

Although adenocarcinomas of the prostate are relatively indolent, some patients with advanced adenocarcinomas show recurrence of treatment-induced neuroendocrine prostate cancer, which is highly aggressive and lethal. Detailed biological features of treatment-induced neuroendocrine prostate cancer have not been characterized owing to limited biopsies/resections and the lack of a cellular model. In this study, we used a unique cellular model (LNCaP/NE1.8) to investigate the potential role of cancer stem cells in treatment-induced neuroendocrine prostate cancer with acquired resistance to hormonal therapy and chemotherapy. We also studied the role of cancer stem cells in enhancing invasion in treatment-induced neuroendocrine prostate cancer cells that recurred after long-term androgen-ablation treatment. Using an in vitro system mimicking clinical androgen-ablation, our results showed that the neuroendocrine-like subclone NE1.8 cells were enriched with cancer stem cells. Compared to parental prostate adenocarcinoma LNCaP cells, NE1.8 cells are more resistant to androgen deprivation therapy and chemotherapeutic agents and show increased cancer cell invasiveness. Results from this study also suggest a potential epigenetic therapeutic strategy using suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, as a chemotherapeutic agent for therapy-resistant treatment-induced neuroendocrine prostate cancer cells to minimize the risk of prostate cancer recurrence and metastasis.
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http://dx.doi.org/10.4103/1008-682X.191518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676429PMC
June 2018

The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma.

Mol Cancer Res 2016 Apr 1;14(4):344-53. Epub 2016 Feb 1.

Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Unlabelled: While prostatic adenocarcinomas are relatively indolent, some patients with advanced adenocarcinomas recur with small cell neuroendocrine carcinoma which is highly aggressive and lethal. Because glycolysis is a feature of malignancy and the degree of glycolysis generally correlates with tumor aggressiveness, we wanted to compare the metabolic differences and the molecular mechanisms involved between the two tumor types. In this study, and based on previous characterization, LNCaP and PC-3 prostate cancer cell lines were selected as models of prostatic adenocarcinoma and small cell neuroendocrine carcinoma, respectively. In addition to measuring glucose consumption, lactate secretion, and reactive oxygen species (ROS) levels, we performed metabolic profiling in these two model systems. The role of CD44 was studied by RNAi and lentivirus-mediated overexpression. Expression of key enzymes in glycolysis was studied using human tissue microarrays containing benign prostate, adenocarcinoma, and small cell neuroendocrine carcinoma. Results showed that glycolytic features of PC-3 cells were higher than that of LNCaP cells. PFKFB4 was overexpressed in human small cell carcinoma tissue versus adenocarcinoma tissue. CD44 regulated glucose metabolism, intracellular ROS, and cell proliferation in PC-3 cells. Inhibition of CD44 also sensitized PC-3 cells to carboplatin. In conclusion, this study suggests different pathways of glucose metabolism contribute to the disparate biologic behaviors of these two tumor types.

Implications: CD44 is an important regulator of glucose metabolism in small cell neuroendocrine carcinoma and may be an important therapeutic target.
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http://dx.doi.org/10.1158/1541-7786.MCR-15-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834240PMC
April 2016

p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma.

Mol Cancer Res 2015 Mar 15;13(3):584-91. Epub 2014 Dec 15.

Department of Pathology and Urology, Jonsson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research, UCLA David Geffen School of Medicine, Los Angeles, California.

Unlabelled: Prostatic small cell neuroendocrine carcinoma (SCNC) is a rare but aggressive form of prostate cancer that is negative for androgen receptor (AR) and not responsive to hormonal therapy. The molecular etiology of this prostate cancer variant is not well understood; however, mutation of the p53 (TP53) tumor suppressor in prostate neuroendocrine cells inactivates the IL8-CXCR2-p53 pathway that normally inhibits cellular proliferation, leading to the development of SCNC. SCNC also overexpresses Aurora kinase A (AURKA) which is considered to be a viable therapeutic target. Therefore, the relationship of these two molecular events was studied, and we show that p53 mutation leads to increased expression of miR-25 and downregulation of the E3 ubiquitin ligase FBXW7, resulting in elevated levels of Aurora kinase A. This study demonstrates an intracellular pathway by which p53 mutation leads to Aurora kinase A expression, which is critically important for the rapid proliferation and aggressive behavior of prostatic SCNC.

Implications: The pathogenesis of prostatic SCNC involves a p53 and Aurora Kinase A signaling mechanism, both potentially targetable pathways.
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http://dx.doi.org/10.1158/1541-7786.MCR-14-0277-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369163PMC
March 2015

Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation.

Asian J Androl 2014 Jul-Aug;16(4):541-4

Departments of Pathology and Urology, Jonsson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Most prostate cancers (PCas) are classified as acinar type (conventional) adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR) and prostate-specific antigen (PSA). There are also scattered neuroendocrine (NE) cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC) after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.
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http://dx.doi.org/10.4103/1008-682X.123669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104077PMC
August 2015

Neuroendocrine differentiation of prostate cancer.

Asian J Androl 2013 May 18;15(3):328-32. Epub 2013 Mar 18.

Departments of Pathology and Urology, Jonsson Comprehensive Cancer Center and Broad Center for Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095–1732, USA.

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http://dx.doi.org/10.1038/aja.2013.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739654PMC
May 2013

PC3 is a cell line characteristic of prostatic small cell carcinoma.

Prostate 2011 Nov 22;71(15):1668-79. Epub 2011 Mar 22.

Department of Pathology, Jonsson Comprehensive Cancer Center and Broad Center for Regenerative Medicine and Stem Cell Biology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1732, USA.

Background: The majority of the prostatic cancers are adenocarcinomas characterized by glandular formation and the expression of luminal differentiation markers androgen receptor (AR) and prostate-specific antigen (PSA). Most adenocarcinomas are indolent and androgen-dependent. Hormonal therapy that inhibits AR signaling produces symptomatic relief in patients with advanced and metastatic adenocarcinomas. Prostatic small cell neuroendocrine carcinoma (SCNC) is a variant form of prostate cancer (PC). In contrast to adenocarcinoma, the tumor cells of SCNC do not form glands and are negative for AR and PSA. SCNC is extremely aggressive and does not respond to hormonal therapy. The purpose of this study was to compare the important and relevant features of two most commonly used PC cell lines, LNCaP and PC3, with prostatic adenocarcinoma and SCNC.

Methods: Xenograft tumors of LNCaP and PC3 were prepared and compared with human prostatic adenocarcinoma and SCNC for the expression of key signaling molecules by immunohistochemistry and Western blot analysis.

Results: LNCaP cells express AR and PSA and their growth is inhibited by androgen withdrawal, similar to human prostatic adenocarcinoma. PC3 cells do not express AR and PSA and their proliferation is independent of androgen, similar to SCNC. Adenocarcinoma cells and LNCaP cells are negative for neuroendocrine markers and stem cell-associated marker CD44 while SCNC and PC3 cells are positive. LNCaP cells have identical cytokeratin profiles to adenocarcinoma while PC3 cells have cytokeratin profiles similar to SCNC.

Conclusion: LNCaP cells share common features with adenocarcinoma while PC3 cells are characteristic of SCNC.
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http://dx.doi.org/10.1002/pros.21383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426349PMC
November 2011

Effects of artemisinin and Artemisia extracts on Haemonchus contortus in gerbils (Meriones unguiculatus).

Vet Parasitol 2011 Jan 16;175(1-2):103-8. Epub 2010 Sep 16.

Department of Biomedical Science and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061-0442, USA.

Haemonchus contortus is a blood-sucking abomasal parasite of small ruminants that is responsible for major losses to producers worldwide. Resistance of this nematode to commercial anthelmintics has produced a demand for alternative control methods. Plants in the genus Artemisia have traditionally been used as anthelmintics and whole plants and plant extracts have demonstrated activity against gastrointestinal nematodes in several studies. In addition, Artemisia annua is the sole commercial source of artemisinin, the raw material used to produce drugs effective against the hemoprotozoan malaria parasites (Plasmodium species). Artemisinin derivatives have also shown efficacy against some trematodes, including Fasciola hepatica and Schistosoma species. In this study, artemisinin was tested for efficacy against H. contortus in a gerbil model of infection. Also tested in the gerbil model were an aqueous extract, an ethanolic extract and the essential oil of A. annua, and an ethanolic extract of Artemisia absinthium. In all experiments, gerbils were infected with 600 third-stage H. contortus larvae. In experiment 1, gerbils were treated orally with 400 milligrams per kilogram body weight (mg/kg BW) artemisinin once or 200mg/kg BW artemisinin daily for 5 days (Days 4-8 post-infection). In experiment 2, gerbils were treated daily for 5 days with 600 mg/kg BW of A. annua ethanolic or aqueous extract. In Experiment 3, gerbils were treated with 1000 mg/kg BW of A. annua or A. absinthium ethanolic extract or with 300 mg/kg BW of A. annua essential oil daily for five consecutive days (Days 4-8 post-infection). No significant effects of treatment were seen with artemisinin or any of the Artemisia species extracts at the dosages studied. The non-ionic surfactant Labrosol(®) was an effective nontoxic solvent for delivery of hydrophilic plant extracts and the lipophilic essential oil used in the study.
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http://dx.doi.org/10.1016/j.vetpar.2010.09.011DOI Listing
January 2011

Efficacy of an orange oil emulsion as an anthelmintic against Haemonchus contortus in gerbils (Meriones unguiculatus) and in sheep.

Vet Parasitol 2010 Aug 18;172(1-2):95-9. Epub 2010 Apr 18.

Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061-0442, USA.

Haemonchus contortus is a blood-sucking abomasal parasite responsible for major losses to small ruminant producers worldwide. The recent increase in populations of anthelmintic resistant parasites has produced a demand for alternative control methods. An orange oil emulsion that has shown activity against plant parasitic nematodes and H. contortus in vitro was assessed for activity against H. contortus in a gerbil model and in the natural ovine host. In gerbil experiments, animals were infected with 600 infective third stage (L3) H. contortus larvae. In one experiment, gerbils were treated with 600 milligrams per kilogram bodyweight (mg/kg BW) orange oil once or daily for 5 days. In a second experiment, gerbils were treated with 1200 mg/kg BW orange oil once or daily for 5 days. On Day 9 post-infection, gerbils were killed, their stomachs removed, and the worms counted. The 600 mg/kg BW dosage caused 7% and 62.6% parasite reduction compared to a control group when given once or daily for 5 days, respectively. The 1200 mg/kg BW dosage of orange oil caused 25% and 87.8% parasite reduction compared to a control group when given once or daily for 5 days, respectively. The difference between the multiple treatment and control group were significant at both dosages (P<0.005). In the sheep trial, 18 lambs were orally inoculated with 10,000 L3 H. contortus. One month later, two groups of six lambs each were dosed with 600 mg/kg BW orange oil either once or daily for 3 days. Fecal egg counts were monitored daily starting on the first day of treatment (Day 0) and continuing for 14 days. Results showed that a single dose of the product caused high fecal egg count reduction (97.4%) compared to control sheep. Egg counts were significantly reduced by Day 2 (P<0.0001). Thus, the orange oil emulsion may potentially be useful in the control of ovine haemonchosis.
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http://dx.doi.org/10.1016/j.vetpar.2010.04.017DOI Listing
August 2010