Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling

Abstract

Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable primary culture of Oct3/4( þ )/Nanog( þ ) lung CSCs fed with CD90( þ ) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.

The prognostic value of combination of CD90 and OCT4 for hepatocellular carcinoma after curative resection

“…Evidences from multiple studies indicated CD90 as a candidate marker of CAFs [13][14][15]32]. Our ndings showed that most of CD90 was mainly expressed in CAFs and some endothelium, which were consistent with previous ndings in pancreatic carcinoma [32], lung cancer [15] and HCC [14]. Like previous studies [13,28], our results demonstrated that CD90 was up-regulated in HCC tissues.…”

“…Moreover, they observed that CAFs secreted IGF-II for paracrine regulation on cancer cells [15]. It is therefore of interest to investigate the correlation of CD90 and OCT4 in HCC patients.…”

“…In addition, Chen et al' study [15] identi ed CD90 as one of marker of CAFs and demonstrated that CD90 + CAFs promoted stem-like properties in lung cancer cells. Evidences from multiple studies indicated CD90 as a candidate marker of CAFs [13][14][15]32]. Our ndings showed that most of CD90 was mainly expressed in CAFs and some endothelium, which were consistent with previous ndings in pancreatic carcinoma [32], lung cancer [15] and HCC [14].…”

“…Sukowati et al [14] found that CAFs isolated from human HCC tissues were positive for CD90. In addition, Chen et al' study [15] identi ed CD90 as one of markers of CAFs and demonstrated that CD90 + CAFs promoted stem-like properties in lung cancer cells. However, the prognostic value of CD90 as the biomarker of CAFs is not well-known.…”

Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides

“…Lung tumors are composed of cancer cells that display varying degrees of proliferation and stemness and are found in specific microenvironmental niches caused by factors such as hypoxia, paracrine signaling, and noncancer-associated cells. [6][7][8][9] These subpopulations of cancer cells are often referred as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) and are consistently more resistant to conventional chemotherapy. 10 While CSCs/ CSLCs were initially considered a distinct subpopulation of cells that if eliminated could cure cancer, it has now been demonstrated that CSCs/CSLCs and non-CSCs can interconvert into each other.…”