Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Abstract

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

Chemokines in cancer related inflammation

“…CCR9 was associated with intestinal melanoma metastasis [112], and CCR10 with spread to LN [113]. CCR5 is expressed by Hodgkin lymphoma [114], in prostate cancer [115] and by mammary tumors [116].…”

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

“…It has been well demonstrated that MSCs are recruited to the site of tumor,9, 11, 12, 13, 14 playing a pivotal role by interfering with other immune cells present in the surrounding tumor tissue. For this reason, it is highly relevant to determine how MSCs exert their immunoregulatory functions.…”

“…Thus, the tumor coopts the regenerative capacity of the host1, 4 resulting in tumor's own survival and proliferation. MSCs can migrate to the sites of inflammation and damage5 within the tumor microenvironment 6, 7, 8, 9, 10. Consistently, MSCs are often found within tumors11 and promote cancer progression and enhance metastasis 9, 12.…”

Les cellules souches mésenchymateuses

“…Les travaux les plus récents se sont focalisés sur les mécanismes qui contribuent aux effets négatifs ou positifs des CSM sur la croissance tumorale (Tableau I). Parmi les études les plus remarquables, on peut citer celle de l'équipe de H. Weinberg qui a montré que les CSM mises au contact de cellules de cancer du sein produisaient la chimiokine CCL5 (connue aussi sous le nom de RANTES, regulated upon activation, normal T-cell expressed, and secreted ), qui était capable d'augmenter de manière spectaculaire la capacité métastatique des cellules tumorales [12]. L'hypersécrétion de CCL5 par les CSM serait secondaire à la production par les cellules tumorales soit d'IGF-1 (insulin-like growth factor-1) [13], soit d'un peptide pro-inflammatoire de 37 acides aminés (LL-37) qui induirait non seulement la production de CCL5, mais aussi celle de l'IL-6 (interleukine-6), l'IL-10 et du VEGF (vascular endothelial growth factor ) et stimulerait l'angiogenèse et la croissance des tumeurs ovariennes [14].…”