Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

Abstract

The lung is one of the deadliest sites of breast cancer metastasis, particularly in patients with triple-negative (TN) disease. We hypothesized that the presence of a TN primary breast tumor induces changes in the extracellular matrix (ECM) and soluble components of the lung microenvironment that support metastatic behavior. SUM159 (TN) and MCF7 (luminal A) breast cancer cells were injected into mice, and primary breast tumors were established prior to assessing metastatic niche changes. We observed increased CD117+ hematopoietic progenitor cells in the bone marrow of SUM159 mice versus MCF7 or control mice (p < 0.05). Relative to mice bearing MCF7 tumors and non-tumor controls, mice bearing SUM159 tumors demonstrated enhanced expression of ECM proteins in the lung (fibronectin, tenascin-c and periostin), with similar changes observed in lung fibroblasts treated with extracellular vesicles (EVs) from TN breast cancer cells (p < 0.05). Exposure to lung-conditioned media (LCM) from SUM159 tumor-bearing mice resulted in increased migration/proliferation of both SUM159 and MCF7 cells relative to the control (p < 0.05). In contrast, LCM from MCF-7 tumor-bearing mice had no such effect. LCM from SUM159 tumor-bearing mice contained 16 unique proteins relative to other LCM conditions, including the metastasis-associated proteins CCL7, FGFR4, GM-CSF, MMP3, thrombospondin-1 and VEGF. These findings suggest for the first time that the TN breast cancer molecular subtype may be an important determinant of premetastatic changes to both the ECM and soluble components of the lung, potentially mediated via breast cancer-derived EVs.

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

“…Furthermore, intratumor hypoxia at primary site promotes PMN formation in secondary organs through enhancement of the expression of several factors and the involvement of exosomes [ 200 , 201 ]. The role of exosomes and MVs from the primary tumor in the communication with PMN cells and modification of ECM has also been widely described [ 202 – 205 ]. Therefore, CSCs may play an important role in PMN formation, but further research is needed to clarify the specific role of the CSC secretome.…”

The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites

“…Growing evidence suggests that the primary tumor also primes distant organs in the development of a premetastatic niche to aid metastasis [10,11]. In mouse models, FN deposition is upregulated in premetastatic niches [4,9].…”

“…In particular, EVs have been reported as a major cause of FN accumulation in the premetastatic niche. They have also been connected to the recruitment of tumor-supporting stromal cells and the enhanced attachment of disseminated tumor cells [10,19]. We recently demonstrated that conditioning pulmonary fibroblasts with EVs from BC cells could drastically alter the subsequent growth of epithelial BC cells in a FN-dependent manner [14].…”

Characteristics of pre-metastatic niche: the landscape of molecular and cellular pathways

“…Extracellular vesicles (EVs), a collective term covering a variety of cell-derived membranous structures, can encapsulate and transport various cellular materials [4][5][6][7][8], mediating the crosstalk between primary tumour microenvironment and the PMN during the early stages of tumour metastasis [9,10]. Tumour-derived EVs can alter the microenvironment in future metastatic sites by directly targeting organ-specific resident cells (liver Kupffer cells [11][12][13][14], hepatic stellate cells (hStCs) [12,15], bone marrow stromal cells [16], tissue-resident macrophages [17,18], lung fibroblasts [14,15,[19][20][21][22][23], lung epithelial cells [14,24], brain astrocytes [19], neurons [19] and microglia [25]). In this way, EVs facilitate PMN formation through induction of cytokines, chemokines and growth factors, extracellular matrix (ECM) remodelling and metabolic reprogramming.…”