Abstract
Simple SummaryBreast cancer progression is prominently regulated by the persistent presence of inflammatory mediators and by stromal cells that are located in the tumors. Here, we connected these two elements by demonstrating that potent pro-inflammatory cytokines (tumor necrosis factor α and interleukin 1β) lead to the conversion of mesenchymal stem cells (MSCs) to inflammatory cancer-associated fibroblasts (CAFs). These inflammation-driven CAFs secrete metastasis-promoting factors that elevate the dispersion, scattering, and migration of breast cancer cells via activation of tumor cell receptors that signal through Ras proteins and via Gαi proteins; the latter receptors were identified as the chemokine receptors CCR2, CCR5, and CXCR1/2. Together, these findings demonstrate that, in breast tumors, chronic inflammation can induce the deleterious process of MSC-to-CAF conversion and thus sets pro-inflammatory mediators as key targets for inhibition, potentially leading to lower levels of pro-metastatic CAFs in breast tumors.The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα + IL-1β (generally 14–18 days) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased abilities to contract collagen gels. Moreover, they gained the phenotype of inflammatory CAFs, as indicated by the reduced expression of α smooth muscle actin (αSMA), increased proliferation, and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell dispersion, scattering, and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5, and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation can induce MSC-to-CAF conversion, leading to the generation of tumor-promoting inflammatory CAFs.
Highlights
Luminal-A breast cancers (BC) are identified by the expression of hormone receptors (estrogen receptors (ER) and progesterone receptors (PR)) and by the absence of HER2 expression; this disease subtype is considered as having a relatively favorable outcome, a considerable number of patients experience local recurrence and metastasis [1,2,3].Similar to many other cancer types, the progression of luminal-A tumors is driven by many elements of the tumor microenvironment (TME) and by the way they interact with each other and with the cancer cells [4,5,6]
Kinetics analyses that were performed until day 19 of cytokine/vehicle treatment provided evidence to a gradual process, leading to an elongated cancer-associated fibroblasts (CAFs)-like morphology of the cells after persistent stimulation of the mesenchymal stem cells (MSCs) by the two cytokines (Figure 1A)
The elongated CAF-like morphology of the cells following tumor necrosis factor α (TNFα) + interleukin 1β (IL-1β) stimulation was clearly distinguished in fluorescent analyses (Figure 1(B1))
Summary
Luminal-A breast cancers (BC) are identified by the expression of hormone receptors (estrogen receptors (ER) and progesterone receptors (PR)) and by the absence of HER2 expression; this disease subtype is considered as having a relatively favorable outcome, a considerable number of patients experience local recurrence and metastasis [1,2,3].Similar to many other cancer types, the progression of luminal-A tumors is driven by many elements of the tumor microenvironment (TME) and by the way they interact with each other and with the cancer cells [4,5,6]. At the TME, major roles are attributed to chronic inflammation [7,8,9,10] and to stromal cells [11,12,13,14,15] in promoting disease progression in many cancer diseases, including luminal-A BC. There is only a limited knowledge on the way these elements interact and affect pro-metastatic activities in this subtype of the disease. A large number of studies indicate that TNFα and IL-1β promote disease progression by acting directly on the tumor cells and by affecting different components of the TME, including immune cells [16,17,18,19,20,21]. The different observations propose that the persistent presence of TNFα and IL-1β at the tumor site contributes to chronic inflammation in BC and that the two cytokines play key roles in advancing disease course
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