Nicotine-enhanced stemness and epithelial-mesenchymal transition of human umbilical cord mesenchymal stem cells promote tumor formation and growth in nude mice

Abstract

Cigarette smoking is a well-known risk factor in the development and progression of malignant diseases. Nicotine, the major constituent in cigarette smoke, has also shown negative effects on stem cells. Mesenchymal stem cells (MSCs) have been widely demonstrated to migrate into tumors and play key roles in cancer progression. However, the mechanisms by which nicotine impacts MSCs and tumorigenesis of lung cancer are still undetermined. In this study we investigated the effects of nicotine on human umbilical cord mesenchymal stem cells (hUC-MSCs) and the impacts of nicotine-treated hUC-MSCs on tumor formation and progression. We found that nicotine has a toxic effect on hUC-MSCs and changes the morphology, inhibits proliferation and promotes apoptosis of hUC-MSCs in a dose-dependent manner. Nicotine-treated hUC-MSCs produce higher level of IL-6. Moreover, nicotine promotes migration, stemness and epithelial-mesenchymal transition (EMT) of hUC-MSCs by inhibiting E-cadherin expression and upregulating mesenchymal markers such as N-cadherin and Vimentin, leading to the induction of stem cell markers Sox2, Nanog, Sall4, Oct4 and CD44. Migration and proliferation of non-small cell lung cancer A549 cells and breast cancer MCF-7 cells are promoted after their coculture with nicotine-treated hUC-MSCs in a cell-cell contact-independent manner. Furthermore, nicotine-treated hUC-MSCs promote tumor formation and growth of A549 cells in nude mice. These studies demonstrated that the enhanced stemness and EMT of hUC-MSCs induced by nicotine are critical for the development of tobacco-related cancers.

The Effects of Nicotine on Development

“…It is well known that the use of combustible tobacco products increases the risk for a malignancy; however, nicotine alone may contribute to treatment resistance and cancer progression. 126,127 An in vitro study using human umbilical cord mesenchymal stem cells treated with nicotine revealed increased migration, enhanced stemness, and increased epithelialmesenchymal transition (EMT), 128 consistent with cellular processes that promote tumor progression. In another study, nicotine induced EMT of breast cancer cells and activated fibroblasts, which enhanced EMT and cancer cell migration.…”

Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function

“…E-cigarette, nicotine patch, and nicotine gum are nicotine replacement therapies for smoking cessation used by these patients ( Hartmann-Boyce et al, 2018 ; Stead et al, 2012 ). Although nicotine, per se, is not a carcinogen, many reports document its tumor-promoting effects ( Li et al, 2017 ; Schaal and Chellappan, 2014 ; Schaal et al, 2018 ) as well as its pro-inflammatory effect, which suppresses the phagocytosis ability of the alveolar macrophages ( Scott et al, 2018 ). Considering our results that clearly demonstrated profound and long-term effects of nicotine on brain metastasis progression, extra caution should be paid in the use of nicotine for smoking cessation.…”

Mesenchymal stem cell‑derived extracellular vesicles promote the in vitro proliferation and migration of breast cancer cells through the activation of the ERK pathway

“…Fresh umbilical cords were collected from healthy donors after obtaining informed consent at the Affiliated Hospital of Jiangsu University. hUC-MSCs were isolated and cultured as described in our previous studies (8,21,31). In brief, umbilical cord blood vessels were carefully removed to retain Wharton's jelly, and the remaining tissue was then cut into 1-mm 3 sized sections with scissors and placed in low glucose Dulbecco's modified Eagle's medium (L-DMEM) (cat.…”

“…Mesenchymal stem cells (MSCs) are multipotent stem cells that can be derived from various tissues, including the umbilical cord, bone marrow and adipose tissue (8)(9)(10)(11). MSCs have the potential to differentiate into various cell types of the mesodermal germ layer, including osteoblasts, adipocytes and chondrocytes (12,13).…”