Abstract
The formation of tumor-promoting premetastatic microenvironment plays a pivotal role on metastatic progression. Understanding how the primary tumor can promote the formation of premetastatic microenvironment in the lung will aid discovery of a final cure for metastatic breast cancer. The murine 4T1 mammary carcinoma cells were injected into the mammary fat pads of the BALB/c mice. Days 0–14 were considered the premetastatic phase. Lung tissues were examined using hematoxylin-eosin staining and transmission electron microscopy. After intravenous injection of TGFβ1 pretreated 4T1 cells, the relative pulmonary vascular permeability was quantified, the extravasation, survival, and proliferation of tumor cells in premetastatic lungs were evaluated, and the levels of S100A8, S100A9, VEGF, and Angpt2 were detected in tumor-bearing mice. The results showed that during the premetastatic phase, an inflammatory response and inflammation-induced vascular hyperpermeability were established, leading to an abnormal pulmonary microenvironment, which facilitated extravasation of circulating tumor cells, and subsequent survival and proliferation of metastatic tumor cells in a TGFβ-dependent manner. Moreover, the expressions of S100A8, S100A9, VEGF, and Angpt2 were increased, and an induction of these genes by TGFβ was further observed in premetastatic lungs. Thus, this study demonstrated that TGFβ promoted the creation of premetastatic microenvironment by modulating certain crucial inflammatory cytokines and growth factors, and finally enhanced the ability of circulating cells to seed the lung.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adamczyk A, Niemiec JA, Ambicka A, Mucha-Małecka A, Mituś J, Ryś J (2014) CD44/CD24 as potential prognostic markers in node-positive invasive ductal breast cancer patients treated with adjuvant chemotherapy. J Mol Histol 45(1):35–45
Akhurst RJ, Hata A (2012) Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 11(10):790–811
Basso D, Fogar P, Plebani M (2013) The S100A8/A9 complex reduces CTLA4 expression by immature myeloid cells: implications for pancreatic cancer-driven immunosuppression. Oncoimmunology 2(6):e24441
Coghlin C, Murray GI (2010) Current and emerging concepts in tumour metastasis. J Pathol 222(1):1–15
Drabsch Y, ten Dijke P (2011) TGF-β signaling in breast cancer cell invasion and bone metastasis. J Mammary Gland Biol Neoplasia 16(2):97–108
Drews-Elger K, Iorns E, Dias A, Miller P, Ward TM, Dean S, Clarke J, Campion-Flora A, Rodrigues DN, Reis-Filho JS, Rae JM, Thomas D, Berry D, El-Ashry D, Lippman ME (2014) Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. Breast Cancer Res Treat 148(1):41–59
Fazilaty H, Gardaneh M, Bahrami T, Salmaninejad A, Behnam B (2013) Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumour Biol 34(4):2019–2030
Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–872
Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71(15):5346–5356
Han M, Xu J, Bi Y, Jiang M, Xu X, Liu Q, Jia J (2013) Primary tumor regulates the pulmonary microenvironment in melanoma carcinoma model and facilitates lung metastasis. J Cancer Res Clin Oncol 139(1):57–65
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Hembruff SL, Jokar I, Yang L, Cheng N (2010) Loss of transforming growth factor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promote mammary tumor progression through macrophage-dependent and -independent mechanisms. Neoplasia 12(5):425–433
Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8(12):1369–1375
Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10(11):1349–1355
Hiratsuka S, Goel S, Kamoun WS, Maru Y, Fukumura D, Duda DG, Jain RK (2011) Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc Natl Acad Sci USA 108(9):3725–3730
Hiratsuka S, Ishibashi S, Tomita T, Watanabe A, Akashi-Takamura S, Murakami M, Kijima H, Miyake K, Aburatani H, Maru Y (2013) Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat Commun 4:1853
Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71(11):3792–3801
Huang Y, Song N, Ding Y, Yuan S, Li X, Cai H, Shi H, Luo Y (2009) Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69(19):7529–7537
Huang H, Bhat A, Woodnutt G, Lappe R (2010) Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 10(8):575–585
Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G (2011) S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 9(2):133–148
Imamura T, Hikita A, Inoue Y (2012) The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer 19(2):118–124
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90
Johnson MR, Wang K, Smith JB, Heslin MJ, Diasio RB (2000) Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. Anal Biochem 278:175–184
Jonkers J, Derksen PW (2007) Modeling metastatic breast cancer in mice. J Mammary Gland Biol Neoplasia 12(2–3):191–203
Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827
Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457(7225):102–106
Liu X, Ni Q, Xu J, Sheng C, Wang Q, Chen J, Yang S, Wang H (2014) Expression and prognostic role of SKIP in human breast carcinoma. J Mol Histol 45(2):169–180
Lukanidin E, Sleeman JP (2012) Building the niche: the role of the S100 proteins in metastatic growth. Semin Cancer Biol 22(3):216–225
McAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28(26):4022–4028
Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11(2):109–119
Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1):66–77
Páez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, Wakatsuki T, Loupakis F, Lenz HJ (2012) Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res 18(3):645–653
Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573
Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225
Sceneay J, Smyth MJ, Möller A (2013) The pre-metastatic niche: finding common ground. Cancer Metastasis Rev 32(3–4):449–464
Shi Y, Liu X, Sun Y, Wu D, Qiu A, Cheng H, Wu C, Wang X (2015) Decreased expression and prognostic role of EHD2 in human breast carcinoma: correlation with E-cadherin. J Mol Histol 46(2):221–231
Silva EJ, Argyris PP, Zou X (2014) Ross K2, Herzberg MC. S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells. Int J Biochem Cell Biol 55C:279–287
Vanharanta S, Massagué J (2013) Origins of metastatic traits. Cancer Cell 24(4):410–421
Varadhachary GR, Raber MN (2014) Cancer of unknown primary site. N Engl J Med 371(8):757–765
Yan HH, Pickup M, Pang Y, Gorska AE, Li Z, Chytil A, Geng Y, Gray JW, Moses HL, Yang L (2010) Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res 70(15):6139–6149
Ye Y, Han X, Guo B, Sun Z, Liu S (2013) Combination treatment with platycodin D and osthole inhibits cell proliferation and invasion in mammary carcinoma cell lines. Environ Toxicol Pharmacol 36(1):115–124
Zhu T, Ji Z, Xu C, Peng Z, Gu L, Zhang R, Liu Y (2014) Expression and prognostic role of SGTA in human breast carcinoma correlates with tumor cell proliferation. J Mol Histol 45(6):665–677
Acknowledgments
The authors are grateful for financial support from the National Natural Science Foundation of China (Nos. 81173269 and 81102597).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there are no conflict of interest.
Rights and permissions
About this article
Cite this article
Ye, Y., Liu, S., Wu, C. et al. TGFβ modulates inflammatory cytokines and growth factors to create premetastatic microenvironment and stimulate lung metastasis. J Mol Hist 46, 365–375 (2015). https://doi.org/10.1007/s10735-015-9633-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-015-9633-4