Abstract available in the Journal of Strength and Conditioning Research.

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets.

INTRODUCCIÓN: La supresión androgénica (SA) en el contexto global del manejo terapéutico del cáncer de próstata (CAP), ocupa un lugar cada vez más relevante, por el gran volumen de pacientes que son sometidos a este tipo de tratamiento y su larga duración. El hipogonadismo inducido por la SA prolongada es una de las causas principales de osteoporosis (OP) secundaria en el varón. La pérdida de masa ósea es un efecto secundario de la SA en pacientes con CAP, y su consecuencia clínica es el incremento del riesgo de fracturas óseas, hecho que impacta negativamente en la supervivencia global de estos pacientes.En la actualidad, la prevalencia de OP en pacientes con CAP sometidos a SA durante un período prolongado de tiempo no está bien establecida y tampoco el impacto del tipo de SA, la dinámica de la pérdida de masa ósea ó la localización ideal para evaluar la densitometría ósea.HIPOTESIS Y OBJETIVOS: La SA en pacientes con CAP produce una pérdida de masa ósea que incrementa el riesgo de fractura. La cinética de la pérdida de masa ósea sería variable en el tiempo, aunque finalmente la prevalencia de OP iría incrementándose. Las características propias del CAP y la predilección del esqueleto axial para metastatizar, plantean problemas de interpretación de la densitometría ósea y como consecuencia, el radio distal sería una zona de elección para determinar la pérdida de masa ósea en estos pacientes. Objetivos: 1. Analizar el impacto de la SA continua en la pérdida de masa ósea en pacientes con CAP; 2. Analizar la prevalencia de OP en las diferentes zonas de medición de la densitometría ósea; 3. Analizar el riesgo de fractura ósea en pacientes sometidos a SA continua; 4. Analizar el impacto de la modalidad de tratamiento hormonal en la pérdida de masa ósea; 5. Determinar la cinética de pérdida de masa ósea en pacientes sometidos a manipulación hormonal; 6. Analizar el radio distal como zona de elección en pacientes con CAP y SA.MATERIAL Y MÉTODOS: Entre marzo de 2001 y junio de 2006 se realizaron un total de 560 densitometrías óseas con el mismo equipo detector (Lunar DPX- IQ 4977) a 253 pacientes con cáncer de próstata no metastásico. La DXA se realizó a nivel lumbar, cuello femoral y radio distal. Se consideraron los valores internacionales consensuados por la OMS para la definición de osteoporosis (T-score).RESULTADOS Y CONCLUSIONES: La tasa de OP basal en los pacientes con CAP sin tratamiento hormonal fue del 35%. Este porcentaje se fue incrementando hasta alcanzar el 80% a los 10 años de seguimiento con tratamiento hormonal. Existió una gran variabilidad en cuanto a la zona de medición ósea para detectar la OP, siendo el triángulo de Ward la zona que detectó mayor porcentaje de pacientes con osteoporosis (determinación basal: columna lumbar 18%, cuello femoral 20%, Ward 28%; determinación a los 10 años: lumbar 48%, femoral 62%, Ward 78%). El riesgo de fractura de cadera se duplicó en pacientes tras 5 años de tratamiento hormonal ( RR 3.9; IC 95% 1.8-9.6). No se encontraron diferencias significativas entre las distintas modalidades de tratamiento hormonal (41.4% vs 41.7%). Se objetivó una pérdida ósea más acentuada durante el primer año de tratamiento hormonal que durante el segundo (columna lumbar -4.19 vs -1.38; cuello femoral -2.27 vs -1.75; triángulo de Ward -4.71 vs -2.34). El radio distal tuvo una sensibilidad para detectar osteoporosis del 66.1% frente a otras localizaciones; esta sensibilidad se mantuvo con diferencias estadísticamente significativas cuando se comparó el grupo bajo tratamiento hormonal con el control (p 0.0042). / INTRODUCTION: Androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) represents an important group of patients who undergo this treatment for a long term duration. The hypogonadism induced by ADT is one of the main causes of osteoporosis in men. This increases the risk of bone fractures in these patients, and recent data have demostrated a negative correlation between skeletal fractures and overall survival in patients with PCa undergoing ADT. Currently, the prevalence of osteoporosis in patients with PCa treated with ADT has not been well characterized, as well as the changes in bone loss at the different bone mineral density zones.HYPOTHESIS AND OBJECTIVES: ADT in patients with PCa produces a bone loss that increases the risk of bone fractures. Bone loss dynamics would be variable on time, although finally the prevalence of osteoporosis would increase. The caractheristics of PCa and its affinity to metastize into the central skeleton site, can confuse in the results interpretation and, as a consecuence, distal forearm could be the best bone mineral density zone in this patients. Objectives: 1. To analyze ADT impact in bone loss in patients with PCa; 2. To analyze the prevalence of osteoporosis at the different bone mineral density zones; 3. To analyze bone fracture risk in patients with continuous ADT; 4. To analyze the impact between the different types of ADT; 5. To determine bone mineral loss dynamics in patients with continuous ADT; 6. To analyze the distal forearm as tne best bone mineral density zone in patients with PCa y ADT.MATERIAL AND METHODS: Between march 2001 and june 2006 we have realized 560 DXA with the same detector device (Lunar DPX- IQ 4977) in 253 PCa patients without bone metastasis. DXA was made at the lumbar zone, femoral neck and distal forearm. We used the World Health Organization criteria for the diagnosis of osteoporosis (T-score and Z-score).RESULTS AND CONCLUSIONS. Basal osteoporosis rate in patients with PCa without ADT was 35%. This percentage increased since 80% after ten years of treatment. To detect osteoporosis rates there was a great variability between all bone mineral density zones; Ward´s triangle detected more patients with osteoporosis (basal measure: lumbar zone 18%, femoral neck 20%, Ward´s triangle 28%; 10 years measure: lumbar zone 48%, femoral neck 62%, Ward´s triangle 78%). Hip fracture risk was duplicated in patients after 5 years of ADT (RR 3.9; IC 95% 1.8-9.6). There were no significative statistical differences between ADT options (41.4% vs 41.7%). During the first year of ADT it was realized more bone loss than in the second year of treatment (lumbar zone -4.19 vs -1.38; femoral neck -2.27 vs -1.75; Ward´s triangle -4.71 vs -2.34). The sensibility to diagnose osteoporosis at the distal forearm was 66.1%; at the distal forearm, there were significative statistical differences when the study group (ADT) was compared with control group (p 0.0042).

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets.

Addenda and corrigenda are tipped-in & numbered leaves 281-282. / Copies of author's previously published articles are inserted back end paper. / Bibliography: leaves 222-279. / xiv, 282 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies were performed in the Langendorff-perfused isolated rat heart, using a paradigm in which atrial distension was prevented. The release of natriuretic peptides and endothelin-1, along with cardiac function was monitored during periods of transient ischaemia or hypoxia. Additional studies were performed in patients undergoing cardiac catheterization. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1999?

Diss. (sammanfattning) Umeå : Univ., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Sveriges lantbruksuniv., 2006. / Härtill 4 uppsatser.