Loading...
2 results
Search Results
Now showing 1 - 2 of 2
- Low doses of ionizing radiation activate endothelial cells and induce angiogenesis in peritumoral tissuesPublication . Gil Marques, Filipa; Poli, Maria Esmeralda; Malaquias, João; Carvalho, Tânia; Portêlo, Ana; Ramires, Afonso; Aldeia, Fernando; Ribeiro, Ruy M.; Vitorino, Emília; Diegues, Isabel; Costa, Luis; Coutinho, João; Pina, Maria Filomena; Mareel, Marc; Santos, Susana Constantino RosaPurpose: During radiotherapy the peritumoral tissues are daily exposed to subtherapeutic doses of ionizing radiation. Herein, the biological and molecular effects of doses lower than 0.8 Gy per fraction (LDIR), previously described as angiogenesis inducers, were assessed in human peritumoral tissues. Material and methods: Paired biopsies of preperitoneal adipose tissue were surgically collected from 16 patients diagnosed with locally advanced rectal cancer who underwent neo-adjuvant radiotherapy. One of the biopsies is located in the vicinity of the region where the tumor received the prescribed dose of radiation, and thus exposed to LDIR; the other specimen, outside all beam apertures, was used as an internal calibrator (IC). Microvessel density (MDV) was quantified by immunohistochemistry and the expression of angiogenic, pro-inflammatory, adhesion and oxidative stress genes was assessed by quantitative RT-PCR using exclusively endothelial cells (ECs) isolated by laser capture microdissection microscopy. Results: LDIR activated peritumoral ECs by significantly up-regulating the expression of several pro-angiogenic genes such as VEGFR1, VEGFR2, ANGPT2, TGFB2, VWF, FGF2, HGF and PDGFC and down-regulating the pro-inflammatory IL8 marker. Accordingly, the MVD was significantly increased in peritumoral tissues exposed to LDIR, compared to the IC. The patients that yielded a larger pro-angiogenic response, also showed the highest MVD. Conclusions: LDIR activate ECs in peritumoral tissues that are associated with increased MVD. Although the technological advances in radiotherapy have contributed to reduce the damage to healthy tissues over the past years, the anatomical regions receiving LDIR should be taken into account in the treatment plan report for patient follow-up and in future studies to correlate these doses with tumor dissemination.
- Low doses of ionizing radiation induce angiogenesis : therapeutic implicationsPublication . Gil Marques, Filipa; Santos, Susana Constantino RosaAngiogenesis is the de novo formation of blood vessels from pre-existing ones, and is a process regulated by a fine-tuned balance between molecules that either stimulate or inhibit vessel growth. When this balance is disrupted, vessel formation or regression occurs in an exacerbated manner, which can lead to angiogenesisdependent diseases, such as cancer and ischemia. We have previously demonstrated that doses of ionizing radiation lower than 0.8 Gy, defined here as low doses of ionizing radiation (LDIR), induce angiogenesis by activating endothelial cells. In physiological contexts, LDIR promote angiogenesis during zebrafish development and adult fin regeneration. Using experimental models, LDIR stimulated neovascularization after ischemia induction and promoted tumor growth and metastasis formation by enhancing angiogenesis. These LDIR effects are relevant since they are present during radiotherapy in the peritumoral tissues and for that reason, the main aim of this doctoral thesis was to determine if LDIR induce angiogenesis in human tissues. Material from parietal peritoneum, located in peritumoral tissues, was removed from patients diagnosed with locally advanced rectal cancer who underwent neoadjuvant radiotherapy. According to our data, LDIR activate endothelial cells in peritumoral tissues, which is associated with increased microvascular density. This effect should be considered in the treatment plan report for patient follow-up and in future studies to establish a correlation between these doses and tumor dissemination. Additionally, this work focused on the mechanisms through which LDIR induce angiogenesis. Since adipocytes secrete multiple angiogenic factors and adipokines that induce angiogenesis, the effect of LDIR in modulating the pro-angiogenic potential of adipocytes was investigated. An in vitro model of adipocyte differentiation was used, and our data show that LDIR enhance the angiogenic potential of adipocyte-conditioned medium in vitro and in vivo. Lastly, this work reveals that even though regeneration is often regarded as a recapitulation of post-embryonic development, LDIR accelerate post-embryonic development but not regeneration, suggesting that the physiological context could be a major determinant of the specific phenotype promoted by LDIR.