Radiation and Stemness Phenotype May Influence Individual Breast Cancer Outcomes: The Crucial Role of MMPs and Microenvironment

Abstract

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

“…However, chemotherapy is not the only treatment that can alter the tumor secretome. As shown in a previous study by our research team, the dose of radiation therapy administered in vitro and in vivo affects the expression of several MMPs and their inhibitors [237]. These alterations were related with the molecular profile of breast cancer.…”

“…These alterations were related with the molecular profile of breast cancer. The study not only highlights the fundamental role played by the specific characteristics of each tumor and TME in response to treatment, but also that radiotherapy promotes the secretion of matrix remodeling enzymes involved in the dispersion, invasiveness and metastasis of CSCs and in the EMT process [237]. Additionally, Shen et al demonstrated that chemotherapy induces breast cancer cells to secrete exosome-derived miR-9, miR-195 and miR-203a, which induces CSC phenotypes and expression of stemness-associated genes, thus generating cancer cell communication and self-adaptation to survive treatment [39].…”

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

“…CSCs are a small portion of cells within tumors and important research targets because of their tumorigenic potential and stemness properties [ 96 , 97 ]. CSCs are found mainly in hypoxic niches, with low pH and with less nutrients [ 75 , 98 ], where they can initiate, maintain, and disseminate tumors [ 64 , 96 ]. CSCs are also involved tumor recurrence and metastasis due to their radio- and chemoresistance ability [ 96 , 99 ].…”

“…CSCs are found mainly in hypoxic niches, with low pH and with less nutrients [ 75 , 98 ], where they can initiate, maintain, and disseminate tumors [ 64 , 96 ]. CSCs are also involved tumor recurrence and metastasis due to their radio- and chemoresistance ability [ 96 , 99 ]. This resistance ability is a consequence of their recovery capacity conferred by intrinsic properties of the cells themselves and extrinsic properties from the TME [ 64 ].…”

“…TME is not only essential for the shape, function, development, and growth of tissues [ 96 , 100 , 107 ], but also for maintaining the optimal conditions of CSCs [ 39 , 61 , 96 , 108 ] and promoting tumor growth [ 109 ]. Within the TME, CSCs reside in specific areas known as CSC niches, where they can survive, self-renew, reactivate [ 30 , 61 , 75 , 110 ], and maintain their plasticity due to the autocrine and paracrine signals provided by the TME [ 111 , 112 , 113 ].…”