Abstract
The importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) bearing monocyte markers in tumor metastasis has been well established. Recently, it was reported that these cells possess phenotypic plasticity and differentiate into fibrocytes, very distinct cells that are precursors of tumorigenic myofibroblasts. However, the importance of this transdifferentiation in tumor metastasis has not been explored. Here, we describe the role of MDSC-derived fibrocytes in tumor metastasis that is regulated by Kruppel-like factor 4 (KLF4), a transcription factor that is critical to monocyte differentiation and to promotion of cancer development. Using mouse metastasis models of melanoma and breast cancer, we found that KLF4 knockout was associated with significantly reduced pulmonary metastasis, which was accompanied by decreased populations of MDSCs, fibrocytes and myofibroblasts in the lung. Cause-effect studies by adoptive transfer revealed that KLF4 deficiency in MDSCs led to significantly reduced lung metastasis that was associated with fewer MDSC-derived fibrocytes and myofibroblasts. Mechanistically, KLF4 deficiency significantly compromised the generation of fibrocytes from MDSCs in vitro. During this process, KLF4 expression levels were tightly linked with those of fibroblast-specific protein-1 (FSP-1), deficiency of which resulted in no metastasis in mice as has been previously reported. In addition, KLF4 bound directly to the FSP-1 promoter as determined by chromatin immunoprecipitation and overexpression of KLF4 increased the FSP-1 promoter activities. Taken together, our results suggest that MDSCs not only execute their immunosuppressive function to promote metastatic seeding as reported before, but also boost metastatic tumor growth after they adopt a fibrocyte fate. Therefore, KLF4-mediated fibrocyte generation from MDSCs may represent a novel mechanism of MDSCs contributing to tumor metastasis and supports the feasibility of inhibiting KLF4 or FSP-1 to prevent tumor metastasis.
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Introduction
Myeloid-derived suppressor cells (MDSCs) are a bone marrow-originated heterogeneous population of immature myeloid cells with phenotypic plasticity1 and involved in multiple inflammatory conditions.2, 3 They are broadly defined as CD11b+Gr-1+ or CD11b+Ly6G+ cells in mice, with a wider range of markers in humans. Increased MDSCs are associated with tumor growth and metastasis in both tumor-bearing mice and cancer patients,4 which makes this population a novel therapeutic target.5 Recently, MDSCs were found to be differentiated into fibrocytes,6 a very distinct cell type that may promote tumorigenesis by incorporating into the tumor stromal and differentiating into myofibroblasts.7, 8 In addition, expansion of fibrocytes has been observed in the microenvironment of solid tumors9 and circulation of subjects with metastatic cancer,10 which facilitate tumor metastasis.11 However, the importance and the underlying molecular mechanism of MDSCs transdifferentiation into fibrocytes in tumor metastasis have not been clearly elucidated.
Kruppel-like factor 4 (KLF4) is a transcription factor12 critical to monocyte differentiation,13 and has an oncogenic function in cancer development.14, 15 Recently, we found that KLF4 deficiency in mammary tumor cells compromised the recruitment and function of MDSCs in primary and metastatic tumors, resulting in attenuated tumor development.16 However, whether and how KLF4 in MDSCs, a major component of immunosuppressive cells in tumor microenvironment,17 regulates tumor metastasis has not been reported before.
In this study, we found that KLF4 deficiency in mice led to reduced pulmonary metastasis, which was accompanied by decreased populations of a subset of MDSCs bearing features of CCR2+CD11b+Ly6Gint (CCR2+ MDSCs) and reduced numbers of fibrocytes and myofibroblasts in the lung. Cause-effect studies indicated that KLF4 deficiency in CCR2+ MDSCs was responsible for compromised lung metastasis. Mechanistically, KLF4 regulated the fibrocyte generation from CCR2+ MDSCs in vitro and occupied the fibroblast-specific protein-1 (FSP-1) promoter, which may contribute to increased promoter activities. Taken together, our study demonstrates a critical role of KLF4-mediated fibrocyte generation from CCR2+MDSCs in tumor metastasis, which may provide a therapeutic strategy to treat metastasis by targeting KLF4 or FSP-1.
Results and discussion
KLF4 deficiency in mouse bone marrow drastically reduced lung metastasis that was accompanied by decreased recruitment of CCR2+ MDSCs in the lung
We recently reported that mammary tumor cell-expressing KLF4 facilitated primary tumor growth and pulmonary metastasis.16 The accumulation of MDSCs in bone marrow, spleen and primary tumors were all decreased in mice that were inoculated with breast cancer cells lacking KLF4 expression. However, KLF4 deficiency is restricted to tumor cells in this study, and the effect of KLF4 in MDSCs on tumor metastasis still remains unknown. Therefore, we generated inducible KLF4-knockout mice (Rosa26CreER/KLF4 (flox+/+) mice on C57BL/6 background) and spontaneous KLF4-knockout mice (FSP-1-Cre/KLF4 (flox+/+) mice on BalB/c background). The efficiency of KLF4 knockout in both models was confirmed by quantitative reverse transcriptase–PCR indicating that KLF4 expression in bone marrow was decreased to <10% of that in the wild-type mice (data not shown). We then established metastatic mouse models using B16F10-Luc2 melanoma and 4T1-Luc2 breast cancer cells in these mice. Ten days after intravenous tumor cell inoculation, in vivo bioluminescent imaging showed that the signals of lung metastasis in KLF4-knockout (KLF4−/−) groups were much lower than those in the control (KLF4+/+) groups in both models (Supplementary Figure S1A). Two weeks after tumor inoculation, mice were sacrificed and a significantly decreased incidence of lung metastasis was found in the KLF4−/− groups (Supplementary Figure S1B). Flow cytometric analysis showed that the percentage of MDSCs in bone marrow of the KLF4−/− group was almost the same as the KLF4+/+ group in both of the two metastatic models. In addition, although MDSCs were reduced in spleen and lung after KLF4 was knocked out in these two models, the differences between the KLF4−/− and KLF4+/+ groups were not statistically significant (data not shown).
Note that KLF4 deficiency was systemic in the above mentioned mouse models. To exclusively investigate whether the KLF4-knockout effect on tumor metastasis was contributed by bone marrow KLF4, we performed the same experiments in the B16F10-Luc2 melanoma metastatic model using chimeric mice that had received bone marrow cells from B6 Rosa26CreER/KLF4(lox+/+)/β-actin-EGFP+ donor mice. Similar with the systemic KLF4-knockout mice, average bioluminescence intensity was decreased from 9.31 (±1.92) × 103 photons/s in the lung of control mice to 2.86 (±1.34) × 103 photons/second in the lung of mice with bone marrow KLF4 knockout induced by TAM (Figure 1a, P<0.05). Consistently, drastically decreased numbers of pulmonary metastatic nodules were found in the KLF4−/− group when compared with the KLF4+/+ group (Figure 1b) and metastatic area was also reduced upon KLF4 deficiency in bone marrow (Figure 1c). Similarly, there were still no significant changes of MDSCs in bone marrow, spleen and lung after KLF4 knockout in the bone marrow (data not shown), even though the percentages of MDSCs in the lung were markedly reduced (Supplementary Figure S2A, P=0.165).
MDSCs are heterogeneous. It was recently reported that a subset of MDSCs characterized by CD11b+Gr-1+CD115+ was preferentially recruited to the lung through the CCL2/CCR2 signaling pathway, resulting in facilitation of pulmonary metastasis of mammary tumor.18 We therefore postulated that KLF4 may only regulate a specific subpopulation of MDSCs, such as CCR2+ MDSCs, leading to compromised lung metastasis in our studies. Indeed, in the B16F10 chimeric metastasis model, the CCR2+ MDSC subset decreased from 2.41 (±0.21)% to 0.86 (±0.25)% in lung (Figure 1d, P<0.05), but not in spleen (Supplementary Figure S2B, P=0.057) or bone marrow (data not shown). Consistent with these results in the B16F10 model, CCR2+ MDSCs in lung (Supplementary Figure S3A, P< 0.001), but not in spleen or bone marrow (data not shown), were also significantly reduced in the 4T1 metastatic model. Collectively, these data suggested that KLF4 in bone marrow regulated the pulmonary recruitment of CCR2+ MDSCs, and decreased CCR2+ MDSCs reduced tumor lung metastasis.
KLF4 deficiency in bone marrow was associated with significantly decreased numbers of fibrocytes and myofibroblasts in metastatic lung
MDSCs are well known for their immunosuppressive functions under different pathological conditions including cancer development.19 As discussed above, KLF4 knockout had limited effects on the recruitment of the whole population of MDSCs, but significantly reduced the numbers of CCR2+ MDSC subset in lung. It suggested that the significantly reduced lung metastasis after bone marrow KLF4 knockout was contributed by other factors beyond the immunosuppressive function of CCR2+ MDSCs. Recently it was reported that MDSCs had a high potential to differentiate into fibrocytes.6 As mesenchymal cells that arise from monocyte precursors, fibrocytes have both the inflammatory features of macrophages and the tissue remodeling properties of fibroblasts.20 Circulating fibrocytes can traffic to lungs and differentiate into fibroblasts,21 the precursors of myofibroblast that are crucial tumor stromal component.22 Therefore, there was an intriguing possibility that the CCR2+ MDSCs exerted their ability of promoting metastatic tumor growth mostly by adopting a fibrocyte fate after they were recruited to lung. To test this, we first used B16F10 chimeric metastasis model. As the chimeric mice received EGFP-expressing bone marrow cells, we used COL1A1+CD45+CD11b+EGFP+ and CD11b+α-SMA+EGFP+ to identify bone marrow-derived fibrocytes and myofibroblasts, respectively. The peripheral blood monocytes and lung single cells of the chimeric mice were examined by flow cytometry. As shown in Figure 2a, the percentage of fibrocytes in peripheral blood monocytes dropped from 2.50 (±0.32) % in the KLF4+/+ group to 0.63 (± 0.40) % in the KLF4−/−group (Figure 2a, P<0.05). Although the percentage of fibrocytes and myofibroblasts in the lung was similar between the two groups (KLF4+/+ 2.54(±0.28) % vs KLF4−/− 1.67(± 0.29) % for fibrocytes, P=0.10, KLF4+/+ 17.03(±1.15) % vs KLF4−/− 16.22(± 0.52) % for myofibroblasts, P=0.60), the total cell number of COL1A1+CD45+CD11b+ EGFP+ and CD11b+α-SMA+EGFP+ cells in the KLF4−/−group decreased by 64.30 and 64.34%, respectively (Figure 2b). In parallel with these observations, the immunofluorescent staining of lung sections showed that the numbers of COL1A1+EGFP+ and α-SMA+EGFP+ double positive cells were significantly reduced in the KLF4−/− group when compared to those in the KLF4+/+ group (Figures 2c and d). Consistently, in the 4T1 metastatic model, decreased populations of fibrocytes (COL1A1+CD45+CD11b+) were also observed in peripheral blood monocytes and lung (Supplementary Figure S3B and S3C, P<0.001 and P<0.01). Together, these findings supported our hypothesis that CCR2+ MDSCs are not only preferentially recruited to target organs to prepare for metastatic seeding, but also boost metastatic tumor growth by adopting a fibrocyte fate. In addition, KLF4 regulates both of these two progresses.
KLF4 ablation in CCR2+ MDSCs reduced pulmonary metastasis that was associated with decreased numbers of fibrocytes
To exclude the effect of KLF4-mediated development of MDSCs and to test the direct effect of KLF4-regulated fibrocyte generation from CCR2+ MDSCs on tumor metastasis, a cause-effect study was performed. We sorted this specific MDSC subset from the lungs of B6 Rosa26CreER/KLF4 (flox+/+)/β-actin-EGFP+ mice bearing B16F10 melanoma, mixed with B16F10 tumor cells, and then injected wild-type mice with the mixture intravenously, followed by tamoxifen (TAM) injection to induce KLF4 knockout (Figure 3a). In the control group, mice only received B16F10 tumor cells, but still intraperitoneally injected with TAM or sunflower seed oil as the control. At day 7 after tumor cell inoculation, mice were sacrificed. The gross view and hematoxylin and eosin staining of the lung in the control group showed that there was no difference in the incidence of lung metastasis between the mice administrated with TAM or sunflower seed oil (data not shown). However, the pulmonary metastatic nodules in the KLF4−/− and control groups were drastically fewer than those in the KLF4+/+ group. The percentages of lung metastatic areas in KLF4−/− (2.64 (± 0.16)%) and control group (2.87 (± 0.21)%) were also significantly lower than those in the KLF4+/+ group (11.71 (± 0.88)%; Figure 3b). Note that KLF4 deficiency in CCR2+ MDSCs led to similar metastatic areas in KLF4−/− group as in the control group. The results demonstrated that CCR2+ MDSCs did facilitate the seeding and growth of pulmonary metastatic nodules in a KLF4-dependent manner. Because the transplanted CCR2+ MDSC cells also carried the EGFP marker, we examined their differentiation in the lung by immunofluorescent staining of lung cryosections with COL1A1 and α-SMA antibodies. The results showed that although there was no difference in the total number of EGFP+ cells between the KLF4+/+ and KLF4−/− group (data not shown), COL1A1+EGFP+ cells decreased from 6.20 (±0.66)% in the KLF4+/+ mice to 1.6 (±0.51)% in KLF4 deficient mice (Figure 3c, P<0.001). Similarly, α-SMA+EGFP+ cells also decreased in KLF4−/− mice (KLF4+/+ 4.6 (±0.68)% versus KLF4−/− 1.4 (±0.40)%, P<0.01, Figure 3c), which further supported our speculation that KLF4 regulates the differentiation of CCR2+ MDSCs after they are recruited to the lung in vivo.
KLF4 gene expression was tightly linked with that of FSP-1 in fibrocyte generation from MDSCs
To elucidate the underlying molecular mechanism, we proceeded to examine the role of KLF4 in fibrocyte generation from MDSCs in vitro. Splenocytes from Rosa26CreER/KLF4 (flox+/+) mice were purified followed by fibrocyte generation assay with recombinant murine interleukin-13 and macrophage colony-stimulating factor as previously described.23 4-OH TAM was used to induce KLF4 knockout. Three days after the cytokine treatment, the cells were stained and the numbers of fibrocytes per 1 × 105 splenocytes in each group were counted. While there were 58±7 fibrocytes per 1 × 105 splenocytes in the control group, the number of fibrocytes decreased to 5±2 fibrocytes per 1 × 105 splenocytes in the presence of 5 μm 4-OH TAM (Figure 4a). In the presence of 10 μm of 4-OH, there were no fibrocytes generated from splenocytes (data not shown). Quantitative reverse transcriptase–PCR analysis revealed that expression levels of KLF4 and FSP-1 were significantly elevated after the application of interleukin-13 and macrophage colony-stimulating factor, and KLF4 knockout induced by 4-OH TAM correlated with significant downregulation of FSP-1 expression (Figure 4b). Consistently, the expression levels of FSP-1 in bone marrow, spleen and lung of the chimeric metastatic model were all decreased upon KLF4 knockout (Supplementary Figure 4), accompanied with deceased lung metastasis. FSP-1 is a member of S100 superfamily of calcium-binding proteins whose expression level is strongly associated with an aggressive metastatic phenotype and worse prognosis for patients with various malignancies.24 The causative role of FSP-1 in tumor metastasis has been well established in literature.24, 25 Given the fact that FSP-1 has a specific expression in fibroblasts and is also found in more than 90% of monocytes of the host immune system,26 it is quite possible that there is a lineage link between the two very different cell types. Our in vivo data has shown that the populations of CCR2+MDSCs, fibrocytes and myofibroblasts were highly correlated, suggesting that fibrocytes are the key to connect the host immune cells with fibroblasts in the tumor microenvironment by carrying the expression/function of FSP-1.
To further test our hypothesis, we sorted four different subsets of MDSCs from murine splenocytes based on CD11b and Ly6G signals (Figure 4c) and performed quantitative PCR analysis and fibrocyte generation assay. In agreement with our speculation, the highest expression levels of KLF4, FSP-1 and CCR2 coexisted in CD11b+Ly6Gint MDSCs (namely CCR2+MDSCs, P2 in Figure 4c) among all the MDSC subsets, and this subpopulation showed the most efficient fibrocyte generation as well (Figure 4c). To examine the potential regulation of FSP-1 transcription by KLF4, we first performed chromatin immunoprecipitation assay using two different KLF4 antibodies to examine the direct binding of KLF4 with the FSP-1 promoter. As shown in the left panel of Figure 4d, both KLF4 antibodies but not control immunoglobulin G pulled down a fragment in the FSP-1 promoter region as amplified by PCR. We also generated a ~2.3 kb FSP-1 promoter luciferase reporter construct and performed dual luciferase assays. As shown in the right panel of Figure 4d, overexpression of KLF4 tripled the FSP-1 promoter activity when compared with that of the vector control. Together, these data suggest a direct regulation of FSP-1 expression by KLF4 at the transcription level in the process of fibrocyte generation from CCR2+ MDSCs.
Collectively, our data suggest that KLF4 in bone marrow promotes tumor metastasis by regulating the recruitment of CCR2+ MDSCs, likely in a CCL2/CCR2-dependent manner because KLF4 regulates CCR2 expression.27 In addition, once CCR2+ MDSCs are recruited to the lung, KLF4 further regulates their differentiation into fibrocytes resulting in increased metastatic tumor growth probably dependent on KLF4-mediated FSP-1 expression. This finding uncovered, to our knowledge, a novel mechanism whereby FSP-1 promotes tumor metastasis by fibrocyte generation from MDSCs. One limitation of our study is that we only used KLF4 deficient mouse models. Future experiments with transgenic mice overexpressing KLF4 in bone marrow will further confirm our observations. In addition, to confirm our hypothesis that KLF4 promotes tumor metastasis in a FSP-1 dependent manner, future experiments will be performed to test whether ectopic expression of KLF4 can rescue FSP-1 knockout-induced phenotypes of tumor metastasis. However, in Fsp-1-Cre/KLF4 (flox+/+) mice, KLF4 deficiency was correlated with drastic downregulation of FSP-1 (data not shown). These results not only confirmed regulation of FSP-1 by KLF4, but also supported our overall hypothesis. Finally, further studies are needed to fully characterize the mechanism whereby KLF4 regulates FSP-1 transcription.
References
Manjili MH . Phenotypic plasticity of MDSC in cancers. Immunol Invest 2012; 41: 711–721.
Youn JI, Gabrilovich DI . The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 2010; 40: 2969–2975.
Saleem SJ, Martin RK, Morales JK, Sturgill JL, Gibb DR, Graham L et al. Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. J Immunol 2012; 189: 511–515.
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V . Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12: 253–268.
Waldron TJ, Quatromoni JG, Karakasheva TA, Singhal S, Rustgi AK . Myeloid derived suppressor cells: targets for therapy. Oncoimmunology 2013; 2: e24117.
Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K, Gobel N et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci USA 2009; 106: 17892–17897.
Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM . Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 2007; 282: 22910–22920.
Mehner C, Radisky DC . Triggering the landslide: the tumor-promotional effects of myofibroblasts. Exp Cell Res 2013; 319: 1657–1662.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330: 827–830.
Zhang H, Maric I, Diprima MJ, Khan J, Orentas RJ, Kaplan RN et al. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 2013; 122: 1105–1113.
van Deventer HW, Palmieri DA, Wu QP, McCook EC, Serody JS . Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2. J Immunol 2013; 190: 4861–4867.
Shields JM, Christy RJ, Yang VW . Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem 1996; 271: 20009–20017.
Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H et al. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. Embo J 2007; 26: 4138–4148.
Pandya AY, Talley LI, Frost AR, Fitzgerald TJ, Trivedi V, Chakravarthy M et al. Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res 2004; 10: 2709–2719.
Yu F, Li J, Chen H, Fu J, Ray S, Huang S et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene 2011; 30: 2161–2172.
Yu F, Shi Y, Wang J, Li J, Fan D, Ai W . Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. Int J Cancer 2013; 133: 2872–2883.
Schreiber RD, Old LJ, Smyth MJ . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331: 1565–1570.
Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011; 475: 222–225.
Qu P, Boelte KC, Lin PC . Negative regulation of myeloid-derived suppressor cells in cancer. Immunol Invest 2012; 41: 562–580.
Reilkoff RA, Bucala R, Herzog EL . Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol 2011; 11: 427–435.
Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004; 114: 438–446.
Otranto M, Sarrazy V, Bonte F, Hinz B, Gabbiani G, Desmouliere A . The role of the myofibroblast in tumor stroma remodeling. Cell Adh Migr 2012; 6: 203–219.
Crawford JR, Pilling D, Gomer RH . Improved serum-free culture conditions for spleen-derived murine fibrocytes. J Immunol Methods 2010; 363: 9–20.
Helfman DM, Kim EJ, Lukanidin E, Grigorian M . The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 2005; 92: 1955–1958.
Mishra SK, Siddique HR, Saleem M . S100A4 calcium-binding protein is key player in tumor progression and metastasis: preclinical and clinical evidence. Cancer Metastasis Rev 2012; 31: 163–172.
Cabezon T, Celis JE, Skibshoj I, Klingelhofer J, Grigorian M, Gromov P et al. Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer 2007; 121: 1433–1444.
Alder JK, Georgantas RW 3rd, Hildreth RL, Kaplan IM, Morisot S, Yu X et al. Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol 2008; 180: 5645–5652.
Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009; 15: 50–58.
Zhang W, Chen X, Kato Y, Evans PM, Yuan S, Yang J et al. Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. Mol Cell Biol 2006; 26: 2055–2064.
Acknowledgements
We thank Udai P Singh for technical assistance and Bryan J Mathis for editing of the manuscript. Grant: this work was supported by Research Development Fund (RDF) from University of South Carolina School of Medicine and ASPIRE-I from University of South Carolina to WA.
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Shi, Y., Ou, L., Han, S. et al. Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes. Oncogenesis 3, e129 (2014). https://doi.org/10.1038/oncsis.2014.44
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DOI: https://doi.org/10.1038/oncsis.2014.44
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