Tumour growth, cachexia and metastasis in vivo and in vitro

Author(s)

Rebeka Tomasin

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2014-08-29

Examining board members

Maria Cristina Cintra Gomes Marcondes; Márcia Regina Cominetti; Estela Maria Gonçalves; Clélia Akiko Hiruma Lima; Miguel Arcanjo Areas

• Advisor: Maria Cristina Cintra Gomes Marcondes

Abstract

Cancer is a generic name for a group of over a hundred diseases which share some features. The most remarkable feature in cancer disease is the fast proliferation of abnormal cells beyond their usual boundaries, invasion of surrounding tissues and finally spread to distant organs. Every year, cancer is responsible for over eight million deaths and twelve million new cases are diagnosed. Among all the events associated with the neoplastic progression, metastasis and cachexia are major issues. Metastases, which are tumours growing in secondary sites, account for 90% of all cancer deaths. Cachexia, a paraneoplastic syndrome, is characterized by severe fat and lean mass waste, fatigue and metabolic alterations, jeopardizing the quality of life and reducing the survival of about 50-85% of the cancer patients, depending on the tumour type. Regarding to the therapies, the biggest challenge is still fighting the tumour without harming the host, which is believed to be possible by targeted therapies to specific genes and/or adjuvant treatments, including supplementation and drugs derived from natural compounds, which usually have lower side effects in the host. Knowing these points, this work had two aims: (1) evaluate the effects of Aloe vera and honey in both tumour and host tissues in Walker 256-tumour bearing rats; and, (2) identification of metastasis suppressor genes using a functional in vivo shRNA screen in a triple negative breast cancer syngeneic model. Regarding to the first aim, the results suggested that the combination of Aloe vera and honey selectively modulate proteolysis and oxidative stress, damaging the tumour tissue while protected the host. Moreover, the Aloe vera and honey treatment apparently decreases the metastatic potential in vivo, by simultaneous increase in E-cadherin and decrease in N-cadherin expression, while decreased tumour vascularization. Finally, our results suggested the antitumoral effects observed in vivo are, at least partially, related to the immunomodulatory activity of some Aloe vera¿s compounds. Regarding to the second aim, dozens of putative metastasis suppressor genes were identified. High confidence candidates, which would be further analysed are Mnat1, Snd1, Cul5, Gabbr1, Rorb, Adk, Ccnd3, Gdnf, Nr1d1, Ptprs e Ltah4. Their selection was based on meeting the following requirements: (a) significant decrease at DNA or RNA level in highly aggressive human breast cancer carcinomas and thus, worse prognosis, (b) suggestive biological role, (c) occurrence of a remarkable phenotype during the screen, and (d) significant decrease in expression in more aggressive cancer cell lines (AU)

• FAPESP's process: 10/00714-5 - "Modulatory Effects of Aloe vera and honey in tumour growth"
• Grantee: Rebeka Tomasin
• Support Opportunities: Scholarships in Brazil - Doctorate