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Biological effect of Type I procollagen carboxyterminal propeptide in breast cancer tumor microenvironment / Miguel Filipe Portugal do Canto e Costa ; orient. Duarte Barral

Main Author Costa, Miguel Filipe Portugal do Canto e Secondary Author Barral, Duarte C. Language Inglês. Country Portugal. Publication Lisboa : NOVA Medical School, 2022 Abstract Collagen is the most abundant component of the extracellularmatrix, having a central role in regulating cell behavior, tissue development and providing tensile strength. In the tumor microenvironment, collagen is stiffer than in normal stroma due to increased linearization and crosslinking and increased collagen expression and density is correlated with a worse prognosis. Desmoplasia, a process characteristic of several types of cancer, including breast carcinoma, results in enhanced type I collagen deposition. Production of type I collagen releases P1CP, a well-described robust and sensitive marker for osteoblastic activity in bone metastasis with relevant prognostic value in this disease. However, the bioactive properties of this fragment, regarding tumor progression, have been poorly explored and may represent an area of therapeutic development. Accordingly, this work aimed to explore the biological role of P1CP in breast cancer cell invasion and metastasis formation, as well as its interaction with the innate immune system using in vitro3D spheroid models and in vivozebrafish xenograft models.In the in vitro3D spheroid models of breast cancer cells co-cultured with monocytic cells or derived macrophages, treatment with P1CP led to an overall increase in invasive ability of cancer cells, except when in the presence of M2-like pro-tumoral macrophages. Significant increases of cancer cell invasion in the presence of THP-I, M0-, and M1-like macrophages hint a possible role of P1CP in the modulation of monocyte differentiation and macrophage polarization towards pro-tumoral phenotypes. Experiments conducted in zebrafish xenografts, hint at P1CP as a possible agent in tumor immune evasion, as reflected by the increase in engraftment rate and regulation of macrophage infiltration in the tumor. Moreover, P1CP treatment resulted in a significant increase in metastasis formation in the head and tail of the zebrafish larvae, in MDA-MB-231 breast cancer tumors.Overall, this project enhanced the knowledge on the biological effects of the presence of P1CP in the tumor microenvironment, confirming a role of this fragment in cancer cell invasion and metastasis formation and establishing an interaction with cells from the innate immune system which ultimately might contribute to immune evasion. Understanding the mechanism of action behind these pro-tumoral functions of P1CP could pave the way for the development of new targeted therapies to benefit cancer patients. Topical name TYPE I PROCOLLAGEN CARBOXYTERMINAL PROPEPTIDE
Breast cancer
Academic Dissertations
Portugal
Index terms Dissertação de Mestrado
Investigação Biomédica
Universidade NOVA de Lisboa
NOVA Medical School
2022
Online Resources Click here to access the eletronic resource http://hdl.handle.net/10362/141911
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online
RUN http://hdl.handle.net/10362/141911 Available 20220123

Collagen is the most abundant component of the extracellularmatrix, having a central role in regulating cell behavior, tissue development and providing tensile strength. In the tumor microenvironment, collagen is stiffer than in normal stroma due to increased linearization and crosslinking and increased collagen expression and density is correlated with a worse prognosis. Desmoplasia, a process characteristic of several types of cancer, including breast carcinoma, results in enhanced type I collagen deposition. Production of type I collagen releases P1CP, a well-described robust and sensitive marker for osteoblastic activity in bone metastasis with relevant prognostic value in this disease. However, the bioactive properties of this fragment, regarding tumor progression, have been poorly explored and may represent an area of therapeutic development. Accordingly, this work aimed to explore the biological role of P1CP in breast cancer cell invasion and metastasis formation, as well as its interaction with the innate immune system using in vitro3D spheroid models and in vivozebrafish xenograft models.In the in vitro3D spheroid models of breast cancer cells co-cultured with monocytic cells or derived macrophages, treatment with P1CP led to an overall increase in invasive ability of cancer cells, except when in the presence of M2-like pro-tumoral macrophages. Significant increases of cancer cell invasion in the presence of THP-I, M0-, and M1-like macrophages hint a possible role of P1CP in the modulation of monocyte differentiation and macrophage polarization towards pro-tumoral phenotypes. Experiments conducted in zebrafish xenografts, hint at P1CP as a possible agent in tumor immune evasion, as reflected by the increase in engraftment rate and regulation of macrophage infiltration in the tumor. Moreover, P1CP treatment resulted in a significant increase in metastasis formation in the head and tail of the zebrafish larvae, in MDA-MB-231 breast cancer tumors.Overall, this project enhanced the knowledge on the biological effects of the presence of P1CP in the tumor microenvironment, confirming a role of this fragment in cancer cell invasion and metastasis formation and establishing an interaction with cells from the innate immune system which ultimately might contribute to immune evasion. Understanding the mechanism of action behind these pro-tumoral functions of P1CP could pave the way for the development of new targeted therapies to benefit cancer patients.

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