Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of ∼ 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.
Robert C Smallridge, Laura A Marlow, and John A Copland
Lindsay G Carter, John A D'Orazio, and Kevin J Pearson
Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.
Laura A Marlow, Ilah Bok, Robert C Smallridge, and John A Copland
Anaplastic thyroid carcinoma is a highly aggressive undifferentiated carcinoma with a mortality rate near 100% due to an assortment of genomic abnormalities which impede the success of therapeutic options. Our laboratory has previously identified that RhoB upregulation serves as a novel molecular therapeutic target and agents upregulating RhoB combined with paclitaxel lead to antitumor synergy. Knowing that histone deacetylase 1 (HDAC1) transcriptionally suppresses RhoB, we sought to extend our findings to other HDACs and to identify the HDAC inhibitor (HDACi) that optimally synergize with paclitaxel. Here we identify HDAC6 as a newly discovered RhoB repressor. By using isoform selective HDAC inhibitors (HDACi) and shRNAs, we show that RhoB has divergent downstream signaling partners, which are dependent on the HDAC isoform that is inhibited. When RhoB upregulates only p21 (cyclin kinase inhibitor) using a class I HDACi (romidepsin), cells undergo cytostasis. When RhoB upregulates BIMEL using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIMEL while upregulation of RhoB and only p21 blocks synergy. This bifurcated regulation of the cell cycle by RhoB is novel and silencing either p21 or BIMEL turns the previously silenced pathway on, leading to phenotypic reversal. This study intimates that the combination of belinostat/vorinostat with paclitaxel may prove to be an effective therapeutic strategy via the novel observation that class II/(I) HDACi antagonize HDAC6-mediated suppression of RhoB and subsequent BIMEL, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.
Alberto Fernandez, Michael Brada, Lina Zabuliene, Niki Karavitaki, and John A H Wass
The hypothalamic–pituitary unit is a particularly radiosensitive region in the central nervous system. As a consequence, hypopituitarism commonly develops after radiation treatments for sellar and parasellar neoplasms, extrasellar brain tumours, head and neck tumours, and following whole body irradiation for systemic malignancies. Increasing tumour-related survival rates provide an expanding population at risk of developing hypopituitarism. In this population, long-term monitoring tailored to the individual risk profile is required to avoid the sequelae of untreated pituitary hormonal deficiencies and resultant decrease in the quality of life. This review analyses the pathogenesis, prevalence and consequences of radiation-induced hypopituitarism (RIH) in diverse subgroups at risk. Also discussed is the impact of modern radiotherapy techniques in the prevalence of RIH, the spectrum of endocrine disorders and radiation-induced brain conditions that also occur in patients with RIH.
Anika Nagelkerke, Anieta M Sieuwerts, Johan Bussink, Fred C G J Sweep, Maxime P Look, John A Foekens, John W M Martens, and Paul N Span
Lysosome-associated membrane protein 3 (LAMP3) is a member of the LAMP-family of proteins, which are involved in the process of autophagy. Autophagy is induced by tamoxifen in breast cancer cells and may contribute to tamoxifen resistance. In this study, the significance of LAMP3 for tamoxifen resistance in breast cancer was examined. The methods employed included use of clonogenic assays to assess the survival of MCF7 breast cancer cells with LAMP3 knockdown after tamoxifen treatment and of quantitative real-time PCR of LAMP3 to evaluate its predictive value for first-line tamoxifen treatment in patients with advanced breast cancer. Results show that tamoxifen treatment of MCF7 cells induced LAMP3 mRNA expression. LAMP3 knockdown in these cells increased tamoxifen sensitivity. Evaluation of expression of the autophagy markers, LC3B and p62, after LAMP3 knockdown showed increased expression levels, indicating that cells with LAMP3 knockdown have a suppressed ability to complete the autophagic process. In addition, knockdown of autophagy-associated genes resulted in sensitization to tamoxifen. Next, tamoxifen-resistant MCF7 cells were cultured. These cells had a sevenfold higher LAMP3 mRNA expression, showed elevated basal autophagy levels, and could be significantly resensitized to tamoxifen by LAMP3 knockdown. In patients treated with first-line tamoxifen for advanced disease (n=304), high LAMP3 mRNA expression was associated with shorter progression-free survival (P=0.003) and shorter post-relapse overall survival (P=0.040), also in multivariate analysis. Together, these results indicate that LAMP3 contributes to tamoxifen resistance in breast cancer. Tamoxifen-resistant cells are resensitized to tamoxifen by the knockdown of LAMP3. Therefore, LAMP3 may be clinically relevant to countering tamoxifen resistance in breast cancer patients.
Prem P Dwivedi, Paul H Anderson, John L Omdahl, H Leighton Grimes, Howard A Morris, and Brian K May
The hormone 1,25-dihydroxyvitamin D (1,25D) may play a protective role in prostate cancer. 25-hydroxyvitamin D 1-α hydroxylase (CYP27B1) is the enzyme responsible for the regulation of cellular 1,25D levels. CYP27B1 is substantially repressed in prostate cancer cells. We have investigated the molecular basis for this inhibition. First, we identify a repressive region between −997 and −1200 in the human CYP27B1 promoter following transient transfection analysis in the prostate cancer cell lines DU145, PC3 and LNCaP. Next, we demonstrate a role for the transcription factor growth factor independent-1 (GFI1) in the repression of CYP27B1. Electrophoretic mobility assays with nuclear extracts from prostate cancer cell lines established binding of GFI1 to the sequence 5′-TGGTACAATCATAACTCACTGCAG-3′ present at −997 to −1200 in the repressive region. Site directed mutagenesis of the core GFI1 binding sequence (5′-AATC-3′) substantially increased while forced expression of GFI1 decreased the expression of the CYP27B1 reporter construct. Importantly, GFI1 repression is dependent on an intact GFI1 binding site in the −997 to −1200 region. GFI1 is an oncoprotein known to form a large protein complex with co-repressors that recruit histone deacetylases. We propose that the formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to silencing of either the nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies provide the basis for a more detailed understanding of CYP27B1 repression in prostate cancer cells and could provide a novel insight in future diagnosis and treatment.
Matthew V Abola, Cheryl L Thompson, Zhengyi Chen, Amitabh Chak, Nathan A Berger, John P Kirwan, and Li Li
S E Bulun, K Zeitoun, K Takayama, L Noble, D Michael, E Simpson, A Johns, M Putman, and H Sasano
Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium. Aromatase expression in endometriosis and its inhibition in eutopic endometrium are controlled by the competitive binding of a stimulatory transcription factor, steroidogenic factor-1, and an inhibitory factor, chicken ovalbumin upstream promoter-transcription factor to a regulatory element in the aromatase P450 gene promoter. In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium. The clinical relevance of local aromatase expression in endometriosis was exemplified by the successful treatment of an unusually aggressive form of recurrent endometriosis in a postmenopausal woman using an aromatase inhibitor.
Danielle Meijer, Anieta M Sieuwerts, Maxime P Look, Ton van Agthoven, John A Foekens, and Lambert C J Dorssers
Tamoxifen treatment of estrogen-dependent breast cancer ultimately loses its effectiveness due to the development of resistance. From a functional screen for identifying genes responsible for tamoxifen resistance in human ZR-75-1 breast cancer cells, fibroblast growth factor (FGF) 17 was recovered. The aim of this exploratory study was to assess the predictive value of FGF17 and the receptors FGFR1–4 for the type of response to tamoxifen treatment (clinical benefit) and the duration of progression-free survival (PFS) in patients with recurrent breast cancer. mRNA levels of FGF17 and FGFR1 – 4 were quantified by real-time reverse transcriptase PCR in 285 estrogen receptor-positive breast carcinomas with clinical follow-up. All patients had recurrent disease and were treated with tamoxifen as first-line systemic therapy for local or distant relapse. FGF17 and FGFR1–3 mRNA levels had no significant predictive value for this group of patients. However, high FGFR4 mRNA levels analyzed as a continuous log-transformed variable predicted poor clinical benefit (odds ratio=1.22; P=0.009) and shorter PFS (hazard ratio=1.18; P<0.001). In addition, in multivariable analysis, the predictive value of FGFR4 was independent from the traditional predictive factors. Our analyses show that FGFR4 may play a role in the biological response of the tumor to tamoxifen treatment. In addition, as altered expression of FGF17 causes tamoxifen resistance in vitro, the FGF signaling pathway could be a valuable target in the treatment of breast cancer patients resistant to endocrine treatment.
Wael K Al-Delaimy, Shirley W Flatt, Loki Natarajan, Gail A Laughlin, Cheryl L Rock, Ellen B Gold, Bette J Caan, Barbara A Parker, and John P Pierce
IGF1, IGF-binding protein-3 (IGFBP-3), IGFBP-1, insulin, leptin, and adiponectin have been inconsistently associated with breast cancer incidence. We explore how these factors are related to breast cancer recurrence and how tamoxifen treatment is related to IGF1 levels among breast cancer survivors in the Women's Healthy Eating and Living (WHEL) study. A nested case–control design was used to match breast cancer cases (who had an additional breast cancer event) to controls. Baseline blood samples from 510 matched cases and controls were analyzed for IGF1 levels; a subset of 188 pairs were analyzed for five other hormones and binding proteins. Median follow-up was 7.3 years. Matching was on recruitment site, cancer stage, age at cancer diagnosis, dates of cancer diagnosis, and randomization. Cox proportional hazards regression models, stratified on case–control pair, were used to assess the associations. Insulin, IGFBP-1, IGFBP-3, leptin, and adiponectin did not significantly predict recurrence of breast cancer. IGF1 was positively, but not significantly, associated with recurrence (hazard ratio (HR): 1.33 (95% confidence interval (CI) 0.98–1.81)) in the unadjusted analyses. Adjusting for menopausal status and tamoxifen use attenuated the HR to 1.07 (95% CI 0.76–1.40). Analyses of case–control pairs with discordant tamoxifen use show opposing HR: IGF1 predicts higher risk of recurrence if cases did not receive tamoxifen treatment. In conclusion, no significant association was found between IGF1 levels, or other related factors, and risk of additional breast cancer among breast cancer survivors. Tamoxifen can confound analysis of IGF1 and recurrence. This supports re-evaluating significance of IGF1 to breast cancer recurrence.