ABSTRACT
Context and aim:
Mesenchymal stem cells (MSC) are multipotent cells displaying a variety of roles. MSC in the lung tumor stroma (T-MSC) have been found to be functionally different from MSC isolated from normal adjacent tissue (N-MSC) and to increase the metastatic potential of the tumor.
We hypothesized that tumor cells can induce N-MSC evolution into T-MSC. Our group previously observed that T-MSC highly expressed various genes. We selected 11 genes involved in angiogenesis, immunomodulation or which were the most highly induced in T-MSC. The aim of the study was to analyze the expression of the 11 genes in N-MSC from lung carcinoma patients, cultured with and without tumor-initiating cells (TIC).
Methods:
Human N-MSC, T-MSC, and TIC were isolated from squamous cell carcinoma. N-MSC and paired TIC were co-cultivated at different ratios, in direct and transwell co-culture and studied at various incubation times. After co-culture, we analyzed the phenotype of N-MSC by fluorescence-activated cell sorting. Furthermore, the expression of the 11 genes of N-MSC assessed by real-time PCR was compared with that of paired T-MSC.
Results:
After co-culture, N-MSC kept a similar phenotype to the control N-MSC. By contrast, the gene expression of N-MSC was modulated by TIC. Three distinct patterns were found :
i) Genes showing early induction of expression, in direct and transwell co-culture, according to N-MSC : TIC ratio.
ii) Genes showing late induction of expression, in direct and transwell co-culture, according to N-MSC : TIC ratio.
iii) Genes showing no direct modulation by TIC
Conclusions:
TIC can modulate the expression of the 11 selected genes in N-MSC in three distinct ways. Among the inducible genes, the degree of up-regulation was dependent on N-MSC : TIC ratio and appeared in both direct and transwell co-cultures, suggesting a mechanism induced by soluble factors secreted by TIC. TIC are at least partially responsible for the evolution of N-MSC into T-MSC.