Biological Characteristics and Genetic Heterogeneity between Carcinoma-Associated Fibroblasts and Their Paired Normal Fibroblasts in Human Breast Cancer

Abstract

BackgroundThe extensional signals in cross-talk between stromal cells and tumor cells generated from extracellular matrix molecules, soluble factor, and cell-cell adhesion complexes cooperate at the extra- and intracellular level in the tumor microenvironment. CAFs are the primary type of stromal cells in the tumor microenvironment and play a pivotal role in tumorigenesis and development. Hitherto, there is hardly any systematic analysis of the intrinsic relationship between CAFs function and its abnormal signaling pathway. The extreme complexity of CAFs’ features and their role in tumor development are needed to be further investigated.Methodology/Principal FindingsWe primary cultured CAFs and NFs from early stages of breast cancer tissue and identified them using their biomarker by immunohistochemistry for Fibronectin, α-SMA and FAP. Microarray was applied to analyze gene expression profiles of human breast CAFs and the paired NFs. The Up-regulated genes classified by Gene Ontology, signal pathways enriched by DAVID pathway analysis. Abnormal signaling pathways in breast cancer CAFs are involved in cell cycle, cell adhesion, signal transduction and protein transport being reported in CAFs derived from other tumors. Significantly, the altered ATM signaling pathway, a set of cell cycle regulated signaling, and immune associated signaling are identified to be changed in CAFs.Conclusions/SignificanceCAFs have the vigorous ability of proliferation and potential of invasion and migration comparing with NFs. CAFs could promote breast cancer cell invasion under co-culture conditions through up-regulated CCL18 and CXCL12. Consistently with its biologic behavior, the gene expression profiling analyzed by microarray shows that some of key signaling pathways, such as cell cycle, cell adhesion, and secreting factors play an important role in CAFs. The altered ATM signaling pathway is abnormally active in the early stage of breast cancer. The set of immune associated signaling may be involved in tumor cell immune evasion.

Correlation between serum level of chemokine (C-C motif) ligand 18 and poor prognosis in breast cancer

“…Previous studies have shown that CCL-18 also has the ability affect tumorigenesis, and can affect the grade and prognosis of ovarian, colon, and gastric cancers. In the treatment of breast cancer with carcinoma-associated fibroblast (CAF) regimen, Peng et al (2013) found that breast cancer cells co-cultured with CAF resulted in increased CCL-18 secretion, which promoted the invasion and metastasis of breast cancer cells. Furthermore, Nariţa et al (2011) found that breast cancer patients with elevated serum CCL-18 levels were associated with poor disease prognosis.…”

Galectin-1 knockdown in carcinoma-associated fibroblasts inhibits migration and invasion of human MDA-MB-231 breast cancer cells by modulating MMP-9 expression

“…CAFs and normal fibroblasts (NFs) were isolated from breast tumor tissues and their normal counterparts as described previously [1,11]. The normal counterparts were defined in the noncancerous region of breast tissue at least 2 cm away from the outer tumor margin.…”

Anatomical information for intercostobrachial nerve preservation in axillary lymph node dissection for breast cancer

“…Based on data collected by the World Health Organization (WHO), 1.4 million women suffered from breast cancer in 2006, and 0.4 million patients died of the cancer (Smigal et al, 2006). In China, the mortality and morbidity of breast cancer has increased annually, and there is now 1 death every 12 min (Peng et al, 2013) and more than 40 in 100,000 women are diagnosed with breast cancer per year in some cities (Leidenius et al, 2003;Zhao et al, 2013). Even worse, the morbidity of breast cancer has been increasing rapidly, by about 3 to 4% every year (Yan et al, 2013).…”