Παθολογική φυσιολογία οστικών μετασταστάσεων στους καρκίνους του μαστού και του προστάτη σε in vivo μοντέλα μυών: επίδραση ορμονικών αναλόγων

Abstract

Pathophysiology of Bone metastases in breast and prostate cancerwith the aid of in vivo mice models; Effect of hormonal analoguesBone metastases are a frequent compilation of cancer, occurringin up to 70 percent of patients with advanced breast and prostate cancer.An extensive line of research has documented that bones constitutes afavorable microenvironment for homing prostate and breast cancercells. Metastases can be osteoblastic, osteolytic, or mixed; they resultfrom increased osteoclastic activity due to an imbalance betweenRANK ligand expression and OPG expression. In breast cancer,osteolytic lesions are most common, whereas in prostate cancer,osteoblastic lesions predominate. In the present work we tested:• The anticancer effects of dexamethasone (DEX), octreotide(OCT), docetaxel (DOC) and their combination on the TRAMP-C1prostate cancer model, in vitro and in vivo.• The anticancer effects of DEX, OCT, adriamycin (ADR) andtheir combination on 4T1 breast cancer model, in vitro and in vivo.• TRAMP-C1 and 4T1 cells were first characterized forsomatostatin receptors (SSTR 1-5) expression and then inoculated ontothe femur of C57Bl and BALB/c mice, respectively. Investigationprotocols included TRAMP-C1 and 4T1 cell proliferation, migrationand invasion assays, in vitro, and the analysis of radiographic images ofbone lesions and the survival of diseased animals.We documented that:• The TRAMP-C1 cells express the SSTR-1, -2, -3 and -5 and arecapable of producing osteoblastic lesions onto the femur of C57Blmice. DEX, OCT and DOC exerted significant anticancer effects onTRAMP-C1 cell proliferation, invasion and migration assays, in vitro.The triple combination treatment scheme (DEX-OCT-DOC) showed asignificant synergistic/additive anticancer effects, reducing by 5-foldthe dose of DOC required for maximal anticancer effects, in vitro. Inaddition, the triple combination regimen produced significantanticancer effects on TRAMP-C1 cell invasion assays better than anysingle agent treatment scheme, with the exception of DEX, whichproduced the maximal inhibitory effect on TRAMP-C1 cell invasionassay. Furthermore, DEX and OCT, when administered as single orcombination treatment schemes did not produce significant anticancereffects on the overall survival of the diseased animals, according to thecriteria established by NCI [Treated animals vs Controls (T/C >125%)].DOC produced a significant anticancer effect, which reflected to theshrinkage of the bone lesions and to a significant increase of the overallsurvival of diseased animals (T/C = 133%), however, the administration of DEX plus OCT regimen prior to DOC therapysignificantly improved the DOC anticancer effects on bone lesions andoverall survival (T/C = 150%). This data suggest that neoadjuvantadministration of DEX plus OCT regimen can improve the anticanceractions of DOC on TRAM-C1 prostate cancer models in vitro and invivo.• The 4T1 cells express the SSTR-2, -3, -4 and -5 and are capableof producing osteolytic lesions onto the femur of BALB/c mice. OCTand DEX induce a dose dependent cell death in vitro. When OCTcombined with DEX showed an antagonistic effect on 4T1 cell line.The combination of OCT plus DEX was ineffective on growthinhibition. The combination of OCT and DEX with ADR had also anantagonistic effect in 4T1 cell line. On the other hand, the singletreatment schemes revealed that the invasion capacity of 4T1 cells wasinhibited by 26% using DEX, by 15% using OCT, and increased by13.2% using ADR single- agent treatment schemes. However, the triplecombination treatment scheme resulted in stimulation by 37.3% of the4T1 cell invasion capability.OCT does not result in significant increase of lifespan of the 4T1 bearing mice, as a single agent (T/C = 105.3%). When we treated 4T1breast cancer bearing mice with DEX and DEX plus OCT, theirmedium survival time (MST) was reduced (T/C= 97.4 % and 94.7 %respectively) to the MST of the untreated animal group (controlT/C=100%). On the other hand, when ADR was used alone, asignificant increase to the lifespan of the mice (T/C = 144.7 %).However, when all three drugs were used in combination, the antitumoractivity of ADR was neutralized (T/C = 110.5%). Also, the animalstreated with combination of the drugs developed more extensiveosteolytic bone destruction than the untreated animals or the animalstreated with one drug alone. This data indicated that the combination ofOCT with DEX in the treatment of 4T1 mouse breast cancer isineffective. The simultaneous use of these drugs should be carefullyconsidered because they also neutralized the antitumor activity of theADR.