Senescent mesenchymal stem cells promote colorectal cancer cells growth via galectin-3 expression
© Li et al. 2015
Received: 20 January 2015
Accepted: 23 April 2015
Published: 6 May 2015
Cellular senescence is linked to aging and tumorigenesis. The senescence of mesenchymal stem cells (MSCs) may influence the tumor growth, metastasis, and angiogenesis by secreting a variety of cytokines and growth factors.
The conditioned media of adipose derived MSCs (AD-MSCs) stimulated the proliferation of human LoVo colorectal-cancer cells, and the replicative senescent MSCs had the more obvious effects in comparison to that of premature AD-MSCs. Analysis of the factors secreted in the MSCs culture media determined that senescent MSCs expressed and secreted high levels of galectin-3. Galectin-3 expression correlated with the stimulatory effect of senescent AD-MSCs on LoVo cells proliferation, as knockdown of galectin-3 in senescent AD-MSCs significantly reversed the effect of MSCs–mediated growth stimulation of LoVo cells. Furthermore, the simultaneous addition of recombinant galectin-3 to the co-culture systems partially restored the tumor-promoting effect of the senescent AD-MSCs. Analysis of the mechanisms of senescent MSCs and galectin-3 on LoVo cells signal transduction determined that senescent MSCs and exogenous galectin-3 promoted cell growth by activating the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase [ERK]1/2) pathway.
Senescent MSCs may alter the tissue microenvironment and affect nearby malignant cells via cytokine secretion, and galectin-3 is an important mediator of senescent AD-MSC–mediated stimulation of colon cancer cell growth. Therefore, thorough assessment of AD-MSCs prior to their implementation in clinical practice is warranted.
KeywordsCellular senescence Mesenchymal stem cells Galectin-3 LoVo cells
Cellular senescence, a state of irreversible growth arrest, can be triggered by many mechanisms, including telomere shortening, epigenetic derepression of the cyclin-dependent kinase inhibitor 2A/ADP ribosylation factor (INK4a/ARF) locus, and DNA damage . Cellular senescence is linked to aging and tumorigenesis, and has been proposed as a suppressive mechanism against the development of cancer [2, 3]. However, recent studies have revealed that cellular senescence also has tumor-promoting effects, and the accumulation of senescent cells during the aging process in vivo may contribute to the age-related increase in cancer incidence .
Mesenchymal stem cells (MSC), which possess broad and potent multilineage differentiation potential and potent immunoregulatory properties, are the optimal source for stem cell transplant in clinical applications [5, 6]. Similar to other adult somatic cells, long-term culture in vitro leads to MSC senescence, which results in growth arrest and reduced differentiation [7, 8]. The replicative senescence of MSCs is evinced by telomere shortening, enlargement and flattening of the characteristic stem cell morphology, reduced proliferation rate, and altered secretory profile [8, 9]. The function of adult tissue-specific stem cells declines with age, and aged MSCs could be more deleterious as they can greatly impair tissue homeostasis and repair [9, 10]. MSCs from aged patients with coronary artery disease have impaired angiogenic potential and reduced proangiogenic factor secretion . Senescent MSCs may contribute to the physiological decline in tissue homeostasis and to the increased risk of neoplasm during aging .
Recently report showed that MSCs stimulated invasion, survival and tumorigenesis of colorectal cancer cells through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in colorectal cancer cells . In this study, we showed that replicative senescent AD-MSCs significantly promoted the proliferation of LoVo colorectal-cancer cells in comparison to premature AD-MSCs, and the expression of galectin-3, a powerful modulator of cell migration and spread in carcinoma cells, correlated with the stimulatory effect of senescent AD-MSCs on colorectal cancer cells proliferation. Therefore, thorough assessment of AD-MSCs prior to their implementation in clinical practice is warranted.
Characterization of P30-MSCs
CM-P30 promoted colon cancer cell proliferation
Galectin-3 contributed to P30-MSC stimulation of colon cancer cell growth
To examine whether galectin-3 secretion in P30-MSCs stimulates LoVo cell proliferation, we blocked galectin-3 expression in P30-MSCs with a galectin-3–specific siRNA. Q-PCR and ELISA data showed that LGALS3 mRNA expression was decreased and that galectin-3 secretion in CM-P30 was significantly reduced following siRNA treatment (Fig. 3c, d).
P30-MSCs promoted ERK1/2 activation in colon cancer cells
Recent studies have shown that a pool of molecules secreted by senescent cells, referred to as having the senescence-associated secretory phenotype (SASP), is associated with arrest of cell proliferation and may contribute to it via the autocrine/paracrine pathways [10, 17]. Our data revealed that the MSCs had the typical senescence-associated characteristics and SASP after repeated passage, marked by the appearance of senescence-associated morphological features, decreased proliferation, SA-β-Gal positivity, induced p53 and p21 expression, and increased galectin-3 expression. We then showed that CM-P30 promoted colon cancer cell proliferation. In the co-culture experiments, we demonstrated that galectin-3 mediated the promoter effects of AD-MSCs on colon cancer cell proliferation to some extent, as specific knockdown of galectin-3 with siRNA significantly reversed the MSC-mediated stimulation of colon cancer cell growth.
The tumor microenvironment is increasingly regarded as an important regulator of malignant progression of cancer cells . MSCs may secrete a variety of cytokines and growth factors that influence tumor growth, metastasis, and angiogenesis [19, 20]. Karnoub et al.  showed that MSCs play a pivotal role in colon cancer progression and metastasis; when recruited into breast cancer stroma, bone marrow MSCs tended to facilitate breast cancer cell metastasis and regulate cancer stem cell behavior via the secretion of the chemokine CCL5. Recent studies have shown that the CM of MSCs enhances tumor growth, indicating that the factors secreted by MSCs have profound effects on “reprogramming” tumor growth [18, 21], and the senescent umbilical cord MSCs promoted the proliferation and migration of breast cancer cells .
Of the MSC SASP factors, we found that galectin-3 was an important mediator of cancer-promoting activity. A unique chimera-type member of the β-galactoside–binding soluble lectin family with a molecular mass of 29–35 kD, galectin-3 is implicated in a variety of biological functions [23, 24]. Previously, Liu et al. showed that galectin-3 is secreted into the CM of UC-MSCs and is involved in the immunosuppressive function of UC-MSCs . In addition, galectin-3 expression in most cancer cells is increased, and is associated with growth and metastases in pancreatic and breast cancer systems . A recent report  showed that galectin-3 is involved in the nicotine-induced promotion of apoptosis resistance of breast cancer cells and that it promotes cancer cell growth and protects cells from apoptosis induced by chemotherapeutic drugs. Baptiste et al.  showed that galectin-3 was a powerful modulator of cell adhesion and spread in breast carcinoma cells and that the exogenous addition of recombinant galectin-3 promoted the growth of galectin-3–null cells. However, our data showed that recombinant galectin-3 has a weaker effect on cancer cell growth than senescent MSCs, suggesting that other cytokines secreted from senescent MSCs may be associated with the stimulation of colon cancer cell growth.
Lastly, we analyzed the mechanisms of senescent MSCs and galectin-3 on colon cancer cell signal transduction, finding that senescent MSCs and exogenous galectin-3 promoted colon cancer cell growth by activating the MAPK (ERK1/2) pathway. The extracellular signal-regulated kinases (ERK1/2) which are serine/threonine protein kinases, as one of the most important regulator of key cellular processes , involved in carcinogenesis due to their ability to stimulate cell proliferation and survival . The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors . Gao et al.  showed that exogenous galectin-3 induces ERK1/2 phosphorylation in cancer cells, and our results are consistent with this reports.
In summary, our study suggests that senescent MSCs may alter the tissue microenvironment and affect nearby malignant cells via cytokine secretion, and that galectin-3 is an important mediator of senescent AD-MSC–mediated stimulation of colon cancer cell growth. Therefore, thorough assessment of AD-MSCs prior to their implementation in clinical practice is warranted.
Materials and methods
Isolation and preparation of senescent AD-MSCs
The AD-MSCs were isolated and obtained by density gradient centrifugation, approved by the Ethics Committee of the Affiliated Hospital of Guiyang Medical College. Briefly, AD-MSCs were isolated and cultured according to a collagenase digestion protocol. Mononuclear cells were plated in α-minimum essential medium (Invitrogen, Carlsbad, CA, USA) containing 10 % fetal bovine serum (FBS) (HyClone, Utah, USA), and cultured in a humidified incubator containing 5 % CO2 at 37 °C.
AD-MSCs were further cultivated to confluence and were amplified, and replicative senescent cells were passaged serially over 30 passages when the typical senescence-associated morphological features appeared. Passage 3 (P3) and P30 cells were referred to as “young” (P3-MSCs) and “senescent” MSCs (P30-MSCs), respectively.
Characterization of senescent AD-MSCs
Senescence-associated β-galactosidase (SA-β-Gal) staining was performed using an SA-β-Gal staining kit (Cell Signaling Technology, Beverly, MA, USA) according to the manufacturer’s instructions. For the proliferation analysis, MSCs were counted every 24 hours for 5 days using a cell counting kit-8 (CCK-8) (DoJinDo, ShangHai, China). All experiments were performed three times.
AD-MSCs surface marker analysis by flow cytometry was performed on a FACSCalibur unit (Becton Dickinson Biosciences, San Jose, CA, USA); cells were stained with phycoerythrin-conjugated antibodies against CD105, CD73, CD90, CD45 and HLA-DR (Becton Dickinson Biosciences). For osteogenic and adipogenic differentiation, MSCs were incubated with MesenCult Osteogenic or Adipogenic Stimulatory Medium (STEMCELL Technologies, Vancouver, Canada) for 2–3 weeks. Osteogenic and adipogenic differentiation was evaluated using Alizarin Red S and Oil Red O (Sigma-Aldrich, St. Louis, MO, USA) staining, respectively.
p21 and p53 protein levels were analyzed by western blotting. Proteins were extracted from 1 × 106 P3-MSCs or P30-MSCs with 1 ml radioimmunoprecipitation assay (RIPA) buffer (Sigma-Aldrich), separated by 10 % sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), and transferred to Immobilon polyvinyl difluoride (PVDF) membranes. The membranes were incubated with antibody against p21 and p53 (Abcam, Cambridge, MA, USA), followed by goat anti-rabbit horseradish peroxidase (HRP)-conjugated antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and visualized with SuperSignal West Pico Chemiluminescent Substrate (Millipore, Billerica, MA, USA).
Preparation of conditioned medium
To harvest the MSC conditioned medium (CM), 80 % confluent P3-MSC and P30-MSC cultures were extensively washed with phosphate-buffered saline (PBS) and incubated in serum-free culture medium for 24 h. Then, the CM from the P3-MSCs (CM-P3) and P30-MSCs (CM-P30) was collected and concentrated to 1/2× volume with an ultra-filtration membrane with a molecular weight cut-off of 3 kD by centrifuging at 5000 rpm for 30 min at 4 °C. The concentrated CM was then filtered through a 0.22-μm membrane and stored at −80 °C until used.
Cell proliferation assay of colon cancer cells
The human LoVo colon cancer cell line was obtained from the American Type Culture Collection (ATCC). LoVo cells were established from a metastatic nodule resected from a 56-year-old Caucasian male colorectal adenocarcinoma patient .
The LoVo cells were cultured in phenol red-free Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen, Carlsbad, CA, USA) supplemented with 10 % FBS; 2.5 × 103 cells/well were plated in 200μl growth medium in 96-well plates. After 24 h, the medium was replaced with concentrated conditioned medium of CM-P3 and CM-P30 as for 12h, 24 h or 48 h. Tumor cell proliferation was evaluated using Cell Counting Kit-8 according to the manufacturer’s instructions.
Analysis of galectin-3 expression in MSCs
We analyzed galectin-3 (LGALS3) mRNA expression with real-time PCR: total RNA was isolated from 1 × 106 P3-MSCs or P30-MSCs using TRIzol (Invitrogen) according to the manufacturer’s instructions. First-strand complementary DNA was reverse-transcribed using a Reverse Transcriptase MIX Kit (Toyobo, Osaka, Japan). Quantitative real-time PCR was performed in an ABI 7500 Fast Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) using Fast SYBR Green PCR Master Mix (Applied Biosystems). We used the following primer pairs as reported previously : β-actin (forward: 5′-GAAGGTGAAGGTCGGAGTCA-3′, reverse: 5′-GAAGATGGTGATGGGATTTC-3′) and LGALS3 (forward: 5′-CCAAAGAGGGAATGATGTTGCC-3′, reverse: 5′-TGATTGTACTGCAACAAGTGAGC-3′).
Galectin-3 levels in CM-P3 or CM-P30 were measured as described previously . Briefly, the concentrated CM was analyzed using a Human Galectin-3 Platinum ELISA (enzyme-linked immunosorbent assay) Kit (eBioscience, San Diego, CA, USA) according to the manufacturer’s instructions.
To knock down galectin-3 expression, P30-MSCs were transfected with predesigned small interfering RNA (siRNA) (Sigma-Aldrich) using Lipofectamine RNAiMAX reagent (Invitrogen). The respective siRNA sequences of MSCs are as follows: galectin-3 siRNA target site (MSCgal-3▼): 5′-CAC UUU AAC CCA CGC UUC AdTdT-3′ and 5′-UGA AGC GUG GGU UAA AGU GdTdT-3′; negative control sequences (MSCNC): 5′-UUC UCC GAA CGU GUC ACG UTT-3′ and 5′-ACG UGA CAC GUU CGG AGA ATT-3′.
P30-MSCs were seeded in 6-well plates, and then transfected with a final concentration of 40pmol/μl MSCgal-3▼ or MSCNC and incubated for 24 h. Following the incubation and supernatant collection, total RNA or proteins were prepared and quantified as described above. Galectin-3 was quantified using the Human Galectin-3 Platinum ELISA Kit.
Moreover, the addition of recombinant galectin-3 (R&D Systems, Minneapolis, MN, USA) with a final concentration of 50-100nmol/ml to the CM of the galectin-3 knockdown MSCs, and the proliferation of LoVo cells were analyzed.
Western blotting for mitogen-activated protein kinase (MAPK)
LoVo cells were incubated with CM of MSCs treated with siRNA in the presence or absence of U0126, the specific inhibitor of MEK1/MEK2. Proteins were extracted from LoVo cells using RIPA buffer, separated by 10 % SDS-PAGE, and transferred to Immobilon PVDF membranes (Millipore). The membranes were blocked with PBS containing 5 % non-fat dry milk and 0.1 % Tween 20 overnight. After washing, the membranes were incubated with antibodies against phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and total ERK1/2 (tERK1/2) (Cell Signaling Technology, Inc., Danvers, MA, USA), incubated with HRP-conjugated secondary antibody and visualized with SuperSignal West Pico Chemiluminescent Substrate (Millipore).
The data are presented as the mean ± standard deviation from ≥3 experiments analyzed using SPSS 17.0 statistical software (IBM, New York, NY, USA). Analysis of significance between two groups was performed with an unpaired 2-tailed Student t-test; 1-way analysis of variance was used for multiple comparisons. Differences were considered significant when P < 0.05.
ADP ribosylation factor
Dulbecco’s modified Eagle’s medium
Enzyme-linked immunosorbent assay
Extracellular signal-regulated kinase
Fetal bovine serum
Human leukocyte antigen-DR
Cyclin-dependent kinase inhibitor 2A
Mitogen-activated protein kinase
Mesenchymal stem cells
Quantitative polymerase chain reaction
Senescence-associated secretory phenotype
Sodium dodecyl sulfate–polyacrylamide gel electrophoresis
Small interfering RNA
Adipose derived mesenchymal stem cells
This work was supported by the State High-tech Research and Development Plans (Grants: 2011AA020109).
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