The bidirectional tumor - mesenchymal stromal cell interaction promotes the progression of head and neck cancer
- Benjamin A Kansy†1,
- Philip A Dißmann†1,
- Hatim Hemeda1, 2,
- Kirsten Bruderek1,
- Anna M Westerkamp1,
- Vivien Jagalski1,
- Patrick Schuler1,
- Katinka Kansy3,
- Stephan Lang1,
- Claudia A Dumitru1 and
- Sven Brandau1Email author
© Kansy et al.; licensee BioMed Central Ltd. 2014
Received: 13 December 2013
Accepted: 4 August 2014
Published: 12 August 2014
Mesenchymal stromal cells (MSC) are an integral cellular component of the tumor microenvironment. Nevertheless, very little is known about MSC originating from human malignant tissue and modulation of these cells by tumor-derived factors. The aim of this study was to isolate and characterize MSC from head and neck squamous cell carcinoma (HNSCC) and to investigate their interaction with tumor cells.
MSC were isolated from tumor tissues of HNSCC patients during routine oncological surgery. Immunophenotyping, immunofluorescence and in vitro differentiation were performed to determine whether the isolated cells met the consensus criteria for MSC. The cytokine profile of tumor-derived MSC was determined by enzyme-linked immunosorbent assay (ELISA). Activation of MSC by tumor-conditioned media was assessed by measuring cytokine release and expression of CD54. The impact of MSC on tumor growth in vivo was analyzed in a HNSCC xenograft model.
Cells isolated from HNSCC tissue met the consensus criteria for MSC. Tumor-derived MSC constitutively produced high amounts of interleukin (IL)-6, IL-8 and stromal cell-derived factor (SDF)-1α. HNSCC-derived factors activated MSC and enhanced secretion of IL-8 and expression of CD54. Furthermore, MSC provided stromal support for human HNSCC cell lines in vivo and enhanced their growth in a murine xenograft model.
This is the first study to isolate and characterize MSC from malignant tissues of patients with HNSCC. We observed cross-talk of stromal cells and tumor cells resulting in enhanced growth of HNSCC in vivo.
Mesenchymal stromal cells (MSC) are multipotent, fibroblast-like progenitor cells that can differentiate into multiple lineages, including osteogenic, adipogenic and chondrogenic cell types. MSC express specific cell surface markers such as CD29, CD73, CD90 and CD105 while lacking hematopoietic markers such as CD14, CD34 and CD45 . Initially described as multipotent stromal cells originating from the bone marrow, MSC were later isolated from various fetal and adult tissues, including the salivary gland, placenta, umbilical cord blood, muscle, adipose tissue, connective tissue and peripheral blood [2–7]. Recently, MSC were also identified in pathological tissues and were found to be actively recruited towards tumors and inflammatory microenvironments [8–11].
The functions of MSC within the tumor microenvironment are very complex and still require extensive characterization . For instance, MSC can differentiate into endothelial or vascular smooth muscle cells and might be critically involved in angiogenic processes . Furthermore, MSC might have strong immunoregulatory effects on both innate and adaptive immune cells as they were shown to modulate the proliferation of T cells, B cells or natural killer cells by releasing various cytokines and metabolites of the arachidonic acid pathway [14–16]. The strong modulatory potential of MSC is further highlighted by their ability to release either proinflammatory or anti-inflammatory factors in response to different types of stimulation . Altogether, these findings indicate that MSC engage in a multidirectional communication with the other cells of the microenvironment and are likely to play an important role in the progression of solid tumors.
Indeed, a number of recent studies demonstrated that MSC enhanced tumor growth and metastasis in several types of cancer [9, 18–23]. MSC exerted these tumor-promoting effects by enhancing angiogenesis, inducing immunosuppression or inhibiting the apoptosis of tumor cells [22, 24, 25]. In sharp contrast, other studies found that MSC had potent antitumor effects by inhibiting angiogenesis, promoting antitumor immune responses and inducing apoptosis of the cancer cells [26–33]. A possible explanation for this discrepancy may be the variability of MSC depending on the tissue and the microenvironment from which they were isolated . Additionally, some variability might exist between human MSC and MSC derived from murine tissues – which have been used in many of the previous studies. Because of these caveats, the exact effects of human tumor-resident MSC on the progression of human tumors remain unclear and need to be further investigated.
In this study, we isolated for the first time MSC from tumor tissues of patients with head and neck squamous cell carcinoma (HNSCC). The isolated cells met the consensus criteria for MSC  and were successfully maintained and propagated in vitro. These tumor-derived mesenchymal stromal cells (TuMSC) exhibited a proinflammatory phenotype and responded to stimulation by tumor cells with a strong interleukin (IL)-8 release and with CD54 upregulation, respectively. Most importantly, TuMSC significantly enhanced the growth of human HNSCC lines when xenografted into recipient animals in vivo. Our data thus suggest a bidirectional interaction of MSC and tumor cells that, ultimately, results in the progression of HNSCC.
Materials and methods
Human HNSCC tissue was obtained from surgical specimens after patients’ written informed consent using guidelines approved by the Ethics Committee of the University Hospital of Essen.
Isolation of mesenchymal stromal cells
Head and neck cancer tissue samples were collected aseptically in sodium chloride (0.9%; Fresenius Kabi, Bad Homburg, Germany). Subsequently, tumor specimens were washed several times with Ringer’s solution (Braun, Melsungen, Germany) to remove the majority of erythrocytes. Tissues were cut into 1 to 2 mm pieces, washed extensively and digested in Ringer’s solution containing 5 mg/ml collagenase type II (CellSystems, Troisdorf, Germany) for 40 minutes at 37°C with gentle shaking. Tissues were centrifuged at 300 × g for 7 minutes, and the supernatant was discarded. The partially digested tissues were further treated with Ringer’s solution and 33 mg/ml dispase (Roche Applied Science, Mannheim, Germany) for 60 minutes at 37°C. The cell suspension was then centrifuged, and the pellet was resuspended in standard culture medium (high-glucose Dulbecco’s modified Eagle’s medium; Invitrogen, Karlsruhe, Germany) supplemented with 10% fetal bovine serum (Biochrom, Berlin, Germany), 1% penicillin/streptomycin (Invitrogen) and 1% sodium pyruvate (Invitrogen) and was transferred to tissue culture flasks. Nonadherent cells were removed by washing with phosphate-buffered saline 48 hours later and fresh medium was added to the remaining cells. During the culture period, cells were maintained at 37°C in a humidified atmosphere of 5% carbon dioxide. Cells were continuously passaged after reaching subconfluency by StemPro® Accutase® Cell Dissociation Reagent (Invitrogen) treatment for 5 minutes at 37°C. Bone-marrow-derived mesenchymal stromal cells (BMMSC) were obtained by a standard procedure as described previously .
Direct immunofluorescence was performed for flow cytometric cell-surface marker immunophenotyping using the following specific monoclonal antibodies: CD14 PE (clone M5E2), CD19 PE (clone HD37), CD73 PE (clone AD2), CD90 (Thy-1) (clone 5E10) (all BD Bioscience, Heidelberg, Germany), CD34 fluorescein isothiocyanate (clone 581; Invitrogen/Molecular Probes), CD45 PE (clone 5B1; Miltenyi, Bergisch Gladbach, Germany) and CD105 fluorescein isothiocyanate (clone 166707; R&D Systems, Wiesbaden, Germany). To determine nonspecific signals, isotype controls were used at the same concentration as that used for the specific antibody. Analysis was performed using a FACS Canto II Flow Cytometer (BD Bioscience) and the resulting data were processed using Diva 6 software (BD Bioscience).
Cells were immunostained for Vimentin (1:200; mouse monoclonal clone VIM13.2; Sigma-Aldrich, Taufkirchen, Germany), S100A4 (1:100, rabbit polyclonal antibody; Abcam, Cambridge, UK), secondary antibody goat anti-mouse IgG fluorescein isothiocyanate (1:100; Dianova, Hamburg, Germany) and goat anti-rabbit IgG Cy3 bis-NHS ester (Cy3) (1:1,000; Dianova). Cells were examined with an Axioskop 2 microscope with a Ph2 Plan-Neofluar 20×/0.5 objective lens (Carl Zeiss MicroImaging, Göttingen, Germany). Images were generated using an Axiocam MRc microscope camera and Axiovision AxioVS40 Software (Carl Zeiss MicroImaging).
Trilineage in vitro differentiation
Differentiation towards osteogenic, adipogenic and chondrogenic lineage was induced as described previously . In brief, cells were seeded at a density of 3 × 103 cells/cm2 on round glass slides in 12-well culture dishes (Greiner Bio-One, Frickenhausen, Germany). For osteogenic differentiation, cells were cultured for 21 days in Mesenchymal Stem Cell Osteogenic Differentiation Medium (PromoCell, Heidelberg, Germany). Medium change was performed every 3 to 4 days. Cells were finally stained with alizarin red S solution for 2 minutes to confirm the formation of calcium phosphate salts.
For adipogenic differentiation, we used Mesenchymal Stem Cell Adipogenic Differentiation Medium (PromoCell) for 14 days. To examine the generation of oil droplets in the cytoplasm after differentiation, cells were fixed with 10% formalin (Sigma-Aldrich) and stained with Sudan-III (Sigma-Aldrich) for 20 minutes at room temperature. Hematoxylin (Thermo Scientific, Bonn, Germany) was used to visualize nuclei.
Chondrogenic differentiation was induced after 48 hours of culture in standard medium supplemented with dexamethasone, 1 × 10-3 M l-proline (Sigma-Aldrich), 10 ng/ml transforming growth factor-β3 (Sigma-Aldrich) and 1% BD ITS Culture supplement (BD Bioscience). Medium change was performed every 3 to 4 days. To demonstrate the presence of glycosaminoglycans, Alcian blue staining was used. Dried 5 μm cryosections of the micromass pellets were fixed with formalin and washed with phosphate-buffered saline. Staining with Alcian blue 8GX (Roth, Karlsruhe, Germany) was performed at room temperature for 60 minutes.
Cytokine profiling of mesenchymal stromal cells
After isolation and cultivation as described above, medium was exchanged and supernatant was collected from three different patient samples of MSC over a period of 24 hours. Cytokine secretion was analyzed with a bead-based multiplex assay (Bio-Plex; Bio Rad, Hercules, CA, USA) according to the manufacturer’s instructions.
Stimulation of MSC with tumor-conditioned medium
Clinical information for tumor-derived mesenchymal stromal cell donors
Murine xenograft model
where V is volume, w is width, and l is length. After 35 days (45 days for control group), mice were sacrificed and the tumors were analyzed. Early termination at day 35 for the MSC/HNSCC group was required by local animal ethics regulations. Animal experiments were approved by the responsible animal ethics committee of the state of North Rhine-Westphalia and carried out according to German guidelines for experimental animal welfare.
Murine xenograft tumors were stained for Ki-67 and terminal deoxynucleotidyl transferase-dUTP nick end-labeling (TUNEL) as markers for proliferation rates and cell death. Anti-Ki-67 antibody MIB-1 mouse anti-human (1:100; Dako, Hamburg, Germany) was used as primary antibody, followed by peroxidase-conjugated rabbit anti-mouse (1:50; Dianova) and goat anti-rabbit (1:50; Dianova) secondary antibodies. Hematoxylin and eosin counterstaining was performed for nucleus identification. Frequency of Ki-67-positive cells as percent of total cells was calculated using three representative images per sample.
Staining for TUNEL was performed with the Apo-Direct Kit© (BD Bioscience) according to the manufacturer’s instructions. The TUNEL-positive area was calculated with Image J (Fiji, open source, http://imagej.net/Fiji) software.
Isolation and characterization of MSC from HNSCC tissues
Cytokine profiling of TuMSC and modulation by tumor-derived factors
Tumor-derived MSC promote HNSCC growth in a murine xenograft model
The histopathology of HNSCC is characterized by large stromal compartments, which surround the tumor islands. Only recently has it been fully recognized that the growth and progression of carcinomas are not only determined by the intrinsic properties of the tumor cells but critically depend on their interaction with the stromal cells. More recently, MSC have been recognized as important cellular components of the tumor stroma [18, 19]. As such, MSC can promote tumor development and progression by various means . For instance, MSC directly modulate tumor cell biology and enhance proliferation, invasion and metastasis. MSC can also enhance angiogenesis by differentiating into or activating endothelial cells . Finally, MSC have very potent immunoregulatory properties  and may downregulate antitumor immunity by a large variety of immunosuppressive mechanisms [14–16].
One way in which MSC interact with the surrounding cells in the tumor microenvironment is via release of cytokines and chemokines. Consistent with this idea, MCS isolated from our HNSCC patients released large amounts of cytokines. It is also noteworthy that, on a per-cell basis, this release may well exceed production of such cytokines by tumor-infiltrating leukocytes. Cytokine profiling revealed that IL-6, IL-8 and stromal cell-derived factor-1 were the most abundant cytokines secreted by the TuMSC in our study. Interestingly, this group of cytokines has previously been reported to be involved in the recruitment of MSC to the tumor site [8, 11, 42]. Still a matter of debate, however, is whether MSC are actively recruited to the tumor site or derive from tissue-resident precursors. While it appears to be unlikely that the entire stroma of carcinomas is actively recruited from a distant site, elegant studies by several groups indicate at least a partial contribution of bone-marrow derived cells to certain components of the tumor stroma [9, 20].
Irrespective of their origin, once present in the malignant tissue MSC are exposed to tumor cells and are likely to be engaged in a bidirectional interaction with those malignant cells. In support of this hypothesis, we found a dramatic upregulation of IL-8 release and of CD54 expression when TuMSC were exposed to tumor-conditioned medium. These findings are in agreement with a number of other studies demonstrating that MSC can be functionally modulated by tumor-derived factors [43–45].
During recent years, MSC have been isolated from a variety of tissues. Many studies analyzing the interactions of MSC with tumor cells used MSC derived from adipose tissue (a readily available tissue from which MSC can be easily isolated) or from bone marrow (where MSC were originally identified and characterized). While MSC derived from different sources share many common features and properties, some functional heterogeneity does exist depending on the tissue of origin [2, 3, 34]. This heterogeneity might also explain the contradictory findings regarding the effect of MSC on cancer progression . Here, we investigated the effect of MSC derived from bone marrow and from malignant tissues of HNSCC patients on the biology of the tumor cells. We clearly showed that both types of MSC strongly promoted tumor growth when coinjected with HNSCC cells into recipient mice. Histologic observations showed histomorphological differences between the tumors coinjected with MSC and the FaDu-only tumors. Notably, coinjection of MSC results in a higher proliferation and apoptosis throughout the sections, indicating a stimulating and metabolism promoting role of MSC in the tumor microenvironment. Because very few studies have thus far analyzed human tumor-resident MSC, our findings might shed new light on how MSC modulate tumor progression in cancer patients.
In this study, we isolated, expanded and characterized for the first time MSC from human malignant HNSCC tissues. This enabled us to assess basic biological functions of these cells, to investigate their modulation by tumor cells and to explore their effects on the growth of human cancer xenografts in mice. Our findings thus contribute to a better understanding of the tumor–stroma interactions and, ultimately, may stimulate the search for novel therapeutic strategies for HNSCC and other types of cancer.
bone marrow-derived mesenchymal stromal cells
head and neck squamous cell carcinoma
mesenchymal stromal cells
tumor-derived mesenchymal stromal cells
terminal deoxynucleotidyl transferase-dUTP nick end-labeling.
The authors would like to acknowledge Anne-Marie Heider and Petra Altenhoff for providing technical assistance. They are grateful to all patients and clinical colleagues who donated or collected clinical samples.
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