Skip to main content

Advertisement

SpringerLink
Log in

Intratumoral PDGFB gene predominantly expressed in endothelial cells is associated with angiogenesis and lymphangiogenesis, but not with metastasis in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients.

Methods

A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups.

Results

High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFβ, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts.

Conclusion

PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

Publicly available datasets were analyzed in this study. TCGA data can be found here: [https://www.cbioportal.org. /Breast Invasive Carcinoma (TCGA, PanCancer Atlas)]. METABRIC data can be found here: [https://www.cbioportal.org. / Breast Cancer (METABRIC, Nature 2012 & Nat Commun 2016)]. Data sets from each of the GEO databases can be downloaded from the following sites and access numbers: [https://www.ncbi.nlm.nih.gov/geo. / GSE20194/GSE25066/GSE163882/GSE20271/GSE96058/GSE2034/GSE124647/GSE159956/GSE12276/GSE110590].

References

  1. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312. https://doi.org/10.1101/gad.1653708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kohler N, Lipton A (1974) Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res 87:297–301. https://doi.org/10.1016/0014-4827(74)90484-4

    Article  CAS  PubMed  Google Scholar 

  3. Ross R, Glomset J, Kariya B, Harker L (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A 71:1207–1210. https://doi.org/10.1073/pnas.71.4.1207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hannink M, Donoghue DJ (1989) Structure and function of platelet-derived growth factor (PDGF) and related proteins. Biochim Biophys Acta 989:1–10. https://doi.org/10.1016/0304-419x(89)90031-0

    Article  CAS  PubMed  Google Scholar 

  5. Van den Akker NM, Winkel LC, Nisancioglu MH, Maas S, Wisse LJ, Armulik A, Poelmann RE, Lie-Venema H, Betsholtz C, Gittenberger-de Groot AC (2008) PDGF-B signaling is important for murine cardiac development: its role in developing atrioventricular valves, coronaries, and cardiac innervation. Dev Dyn 237:494–503. https://doi.org/10.1002/dvdy.21436

    Article  CAS  PubMed  Google Scholar 

  6. Nystrom HC, Lindblom P, Wickman A, Andersson I, Norlin J, Faldt J, Lindahl P, Skott O, Bjarnegard M, Fitzgerald SM, Caidahl K, Gan LM, Betsholtz C, Bergstrom G (2006) Platelet-derived growth factor B retention is essential for development of normal structure and function of conduit vessels and capillaries. Cardiovasc Res 71:557–565. https://doi.org/10.1016/j.cardiores.2006.05.019

    Article  CAS  PubMed  Google Scholar 

  7. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316. https://doi.org/10.1152/physrev.1999.79.4.1283

    Article  CAS  PubMed  Google Scholar 

  8. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245. https://doi.org/10.1126/science.277.5323.242

    Article  CAS  PubMed  Google Scholar 

  9. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055. https://doi.org/10.1242/dev.126.14.3047

    Article  CAS  PubMed  Google Scholar 

  10. Ehnman M, Ostman A (2014) Therapeutic targeting of platelet-derived growth factor receptors in solid tumors. Expert Opin Investig Drugs 23:211–226. https://doi.org/10.1517/13543784.2014.847086

    Article  CAS  PubMed  Google Scholar 

  11. Furuhashi M, Sjoblom T, Abramsson A, Ellingsen J, Micke P, Li H, Bergsten-Folestad E, Eriksson U, Heuchel R, Betsholtz C, Heldin CH, Ostman A (2004) Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 64:2725–2733. https://doi.org/10.1158/0008-5472.can-03-1489

    Article  CAS  PubMed  Google Scholar 

  12. Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151. https://doi.org/10.1172/JCI18549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bartoschek M, Pietras K (2018) PDGF family function and prognostic value in tumor biology. Biochem Biophys Res Commun 503:984–990. https://doi.org/10.1016/j.bbrc.2018.06.106

    Article  CAS  PubMed  Google Scholar 

  14. Ostman A (2017) PDGF receptors in tumor stroma: Biological effects and associations with prognosis and response to treatment. Adv Drug Deliv Rev 121:117–123. https://doi.org/10.1016/j.addr.2017.09.022

    Article  CAS  PubMed  Google Scholar 

  15. Coltrera MD, Wang J, Porter PL, Gown AM (1995) Expression of platelet-derived growth factor B-chain and the platelet-derived growth factor receptor beta subunit in human breast tissue and breast carcinoma. Cancer Res 55:2703–2708

    CAS  PubMed  Google Scholar 

  16. Bhardwaj B, Klassen J, Cossette N, Sterns E, Tuck A, Deeley R, Sengupta S, Elliott B (1996) Localization of platelet-derived growth factor beta receptor expression in the periepithelial stroma of human breast carcinoma. Clin Cancer Res 2:773–782

    CAS  PubMed  Google Scholar 

  17. Satyananda V, Oshi M, Endo I, Takabe K (2021) High BRCA2 gene expression is associated with aggressive and highly proliferative breast cancer. Ann Surg Oncol 28:7356–7365. https://doi.org/10.1245/s10434-021-10063-5

    Article  PubMed  Google Scholar 

  18. Oshi M, Gandhi S, Tokumaru Y, Yan L, Yamada A, Matsuyama R, Ishikawa T, Endo I, Takabe K (2021) Conflicting roles of EGFR expression by subtypes in breast cancer. Am J Cancer Res 11:5094–5110

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Oshi M, Gandhi S, Huyser MR, Tokumaru Y, Yan L, Yamada A, Matsuyama R, Endo I, Takabe K (2021) MELK expression in breast cancer is associated with infiltration of immune cell and pathological compete response (pCR) after neoadjuvant chemotherapy. Am J Cancer Res 11:4421–4437

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang JL, Oshi M, Endo I, Takabe K (2021) Clinical relevance of stem cell surface markers CD133, CD24, and CD44 in colorectal cancer. Am J Cancer Res 11:5141–5154

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Asaoka M, Patnaik SK, Ishikawa T, Takabe K (2021) Different members of the APOBEC3 family of DNA mutators have opposing associations with the landscape of breast cancer. Am J Cancer Res 11:5111–5125

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu R, Patel A, Tokumaru Y, Asaoka M, Oshi M, Yan L, Ishikawa T, Takabe K (2022) High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer. Breast Cancer Res Treat 193:49–63. https://doi.org/10.1007/s10549-022-06552-0

    Article  CAS  PubMed  Google Scholar 

  23. Wu R, Oshi M, Asaoka M, Huyser MR, Tokumaru Y, Yamada A, Yan L, Endo I, Ishikawa T, Takabe K (2022) APOBEC3F expression in triple-negative breast cancer is associated with tumor microenvironment infiltration and activation of cancer immunity and improved survival. Am J Cancer Res 12:744–762

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tokumaru Y, Oshi M, Katsuta E, Yan L, Satyananda V, Matsuhashi N, Futamura M, Akao Y, Yoshida K, Takabe K (2020) KRAS signaling enriched triple negative breast cancer is associated with favorable tumor immune microenvironment and better survival. Am J Cancer Res 10:897–907

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K (2020) Inflammation is associated with worse outcome in the whole cohort but with better outcome in triple-negative subtype of breast cancer patients. J Immunol Res 2020:5618786. https://doi.org/10.1155/2020/5618786

    Article  PubMed  PubMed Central  Google Scholar 

  26. Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, Nagahashi M, Takabe K (2020) Intra-tumoral angiogenesis is associated with inflammation, immune reaction and metastatic recurrence in breast cancer. Int J Mol Sci 21:6708. https://doi.org/10.3390/ijms21186708

    Article  CAS  PubMed Central  Google Scholar 

  27. Oshi M, Satyananda V, Angarita FA, Kim TH, Tokumaru Y, Yan L, Matsuyama R, Endo I, Nagahashi M, Takabe K (2021) Angiogenesis is associated with an attenuated tumor microenvironment, aggressive biology, and worse survival in gastric cancer patients. Am J Cancer Res 11:1659–1671

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Oshi M, Huyser MR, Le L, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K (2021) Abundance of microvascular endothelial cells is associated with response to chemotherapy and prognosis in colorectal cancer. Cancers 13:1477. https://doi.org/10.3390/cancers13061477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu R, Sarkar J, Tokumaru Y, Takabe Y, Oshi M, Asaoka M, Yan L, Ishikawa T, Takabe K (2022) Intratumoral lymphatic endothelial cell infiltration reflecting lymphangiogenesis is counterbalanced by immune responses and better cancer biology in the breast cancer tumor microenvironment. Am J Cancer Res 12:504–520

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Oshi M, Takahashi H, Tokumaru Y, Yan L, Rashid OM, Matsuyama R, Endo I, Takabe K (2020) G2M cell cycle pathway score as a prognostic biomarker of metastasis in estrogen receptor (ER)-positive breast cancer. Int J Mol Sci 21:2921. https://doi.org/10.3390/ijms21082921

    Article  CAS  PubMed Central  Google Scholar 

  31. Oshi M, Takahashi H, Tokumaru Y, Yan L, Rashid OM, Nagahashi M, Matsuyama R, Endo I, Takabe K (2020) The E2F pathway score as a predictive biomarker of response to neoadjuvant therapy in ER+/HER2- breast cancer. Cells 9:1643. https://doi.org/10.3390/cells9071643

    Article  CAS  PubMed Central  Google Scholar 

  32. Schulze A, Oshi M, Endo I, Takabe K (2020) MYC targets scores are associated with cancer aggressiveness and poor survival in er-positive primary and metastatic breast cancer. Int J Mol Sci 21:8127. https://doi.org/10.3390/ijms21218127

    Article  CAS  PubMed Central  Google Scholar 

  33. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. https://doi.org/10.1038/nature11412

    Article  CAS  Google Scholar 

  34. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Group M, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346–352. https://doi.org/10.1038/nature10983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

    Article  PubMed  Google Scholar 

  36. Brueffer C, Gladchuk S, Winter C, Vallon-Christersson J, Hegardt C, Hakkinen J, George AM, Chen Y, Ehinger A, Larsson C, Loman N, Malmberg M, Ryden L, Borg A, Saal LH (2020) The mutational landscape of the SCAN-B real-world primary breast cancer transcriptome. EMBO Mol Med 12:e12118. https://doi.org/10.15252/emmm.202012118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brueffer C, Vallon-Christersson J, Grabau D, Ehinger A, Hakkinen J, Hegardt C, Malina J, Chen Y, Bendahl PO, Manjer J, Malmberg M, Larsson C, Loman N, Ryden L, Borg A, Saal LH (2018) Clinical value of RNA sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: a report from the population-based multicenter sweden cancerome analysis network-breast initiative. JCO Precis Oncol. https://doi.org/10.1200/PO.17.00135

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679. https://doi.org/10.1016/S0140-6736(05)17947-1

    Article  CAS  PubMed  Google Scholar 

  39. Sinn BV, Fu C, Lau R, Litton J, Tsai TH, Murthy R, Tam A, Andreopoulou E, Gong Y, Murthy R, Gould R, Zhang Y, King TA, Viale A, Andrade V, Giri D, Salgado R, Laios I, Sotiriou C, Marginean EC, Kwiatkowski DN, Layman RM, Booser D, Hatzis C, Vicente Valero V, Fraser Symmans W (2019) SETER/PR: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer. NPJ Breast Cancer 5:16. https://doi.org/10.1038/s41523-019-0111-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Regua A, Papp C, Grageda A, Porter BA, Caza T, Bichindaritz I, Krendel M, Sivapiragasam A, Bratslavsky G, Kuznetsov VA, Kotula L (2021) ABI1-based expression signature predicts breast cancer metastasis and survival. Mol Oncol. https://doi.org/10.1002/1878-0261.13175

    Article  Google Scholar 

  41. Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massague J (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–1009. https://doi.org/10.1038/nature08021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Siegel MB, He X, Hoadley KA, Hoyle A, Pearce JB, Garrett AL, Kumar S, Moylan VJ, Brady CM, Van Swearingen AE, Marron D, Gupta GP, Thorne LB, Kieran N, Livasy C, Mardis ER, Parker JS, Chen M, Anders CK, Carey LA, Perou CM (2018) Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer. J Clin Invest 128:1371–1383. https://doi.org/10.1172/JCI96153

    Article  PubMed  PubMed Central  Google Scholar 

  43. Shi L, Campbell G, Jones WD, Campagne F, Wen Z, Walker SJ, Su Z, Chu TM, Goodsaid FM, Pusztai L, Shaughnessy JD Jr, Oberthuer A, Thomas RS, Paules RS, Fielden M, Barlogie B, Chen W, Du P, Fischer M, Furlanello C, Gallas BD, Ge X, Megherbi DB, Symmans WF, Wang MD, Zhang J, Bitter H, Brors B, Bushel PR, Bylesjo M, Chen M, Cheng J, Cheng J, Chou J, Davison TS, Delorenzi M, Deng Y, Devanarayan V, Dix DJ, Dopazo J, Dorff KC, Elloumi F, Fan J, Fan S, Fan X, Fang H, Gonzaludo N, Hess KR, Hong H, Huan J, Irizarry RA, Judson R, Juraeva D, Lababidi S, Lambert CG, Li L, Li Y, Li Z, Lin SM, Liu G, Lobenhofer EK, Luo J, Luo W, McCall MN, Nikolsky Y, Pennello GA, Perkins RG, Philip R, Popovici V, Price ND, Qian F, Scherer A, Shi T, Shi W, Sung J, Thierry-Mieg D, Thierry-Mieg J, Thodima V, Trygg J, Vishnuvajjala L, Wang SJ, Wu J, Wu Y, Xie Q, Yousef WA, Zhang L, Zhang X, Zhong S, Zhou Y, Zhu S, Arasappan D, Bao W, Lucas AB, Berthold F, Brennan RJ, Buness A, Catalano JG, Chang C, Chen R, Cheng Y et al (2010) The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. Nat Biotechnol 28:827–838. https://doi.org/10.1038/nbt.1665

    Article  CAS  PubMed  Google Scholar 

  44. Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, Vidaurre T, Holmes F, Souchon E, Wang H, Martin M, Cotrina J, Gomez H, Hubbard R, Chacon JI, Ferrer-Lozano J, Dyer R, Buxton M, Gong Y, Wu Y, Ibrahim N, Andreopoulou E, Ueno NT, Hunt K, Yang W, Nazario A, DeMichele A, O’Shaughnessy J, Hortobagyi GN, Symmans WF (2011) A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA 305:1873–1881. https://doi.org/10.1001/jama.2011.593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen JW, Russell RP, Desai T, Fiel-Gan M, Bhat V, de Fátima DGM, Amendola LC, Vasconcelos Z, Brufsky AM, Fournier MV, Tannenbaum SH (2021) RNA expression classifiers from a model of breast epithelial cell organization to predict pathological complete response in triple negative breast cancer. medRrxiv. https://doi.org/10.1101/2021.02.10.21251517

    Article  Google Scholar 

  46. Tabchy A, Valero V, Vidaurre T, Lluch A, Gomez H, Martin M, Qi Y, Barajas-Figueroa LJ, Souchon E, Coutant C, Doimi FD, Ibrahim NK, Gong Y, Hortobagyi GN, Hess KR, Symmans WF, Pusztai L (2010) Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer. Clin Cancer Res 16:5351–5361. https://doi.org/10.1158/1078-0432.CCR-10-1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu SZ, Roden DL, Wang C, Holliday H, Harvey K, Cazet AS, Murphy KJ, Pereira B, Al-Eryani G, Bartonicek N, Hou R, Torpy JR, Junankar S, Chan CL, Lam CE, Hui MN, Gluch L, Beith J, Parker A, Robbins E, Segara D, Mak C, Cooper C, Warrier S, Forrest A, Powell J, O’Toole S, Cox TR, Timpson P, Lim E, Liu XS, Swarbrick A (2020) Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J 39:e104063. https://doi.org/10.15252/embj.2019104063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, Thennavan A, Wang C, Torpy JR, Bartonicek N, Wang T, Larsson L, Kaczorowski D, Weisenfeld NI, Uytingco CR, Chew JG, Bent ZW, Chan CL, Gnanasambandapillai V, Dutertre CA, Gluch L, Hui MN, Beith J, Parker A, Robbins E, Segara D, Cooper C, Mak C, Chan B, Warrier S, Ginhoux F, Millar E, Powell JE, Williams SR, Liu XS, O’Toole S, Lim E, Lundeberg J, Perou CM, Swarbrick A (2021) A single-cell and spatially resolved atlas of human breast cancers. Nat Genet 53:1334–1347. https://doi.org/10.1038/s41588-021-00911-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. https://doi.org/10.1016/j.cels.2015.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Aran D, Hu Z, Butte AJ (2017) xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 18:220. https://doi.org/10.1186/s13059-017-1349-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, Ziv E, Culhane AC, Paull EO, Sivakumar IKA, Gentles AJ, Malhotra R, Farshidfar F, Colaprico A, Parker JS, Mose LE, Vo NS, Liu J, Liu Y, Rader J, Dhankani V, Reynolds SM, Bowlby R, Califano A, Cherniack AD, Anastassiou D, Bedognetti D, Mokrab Y, Newman AM, Rao A, Chen K, Krasnitz A, Hu H, Malta TM, Noushmehr H, Pedamallu CS, Bullman S, Ojesina AI, Lamb A, Zhou W, Shen H, Choueiri TK, Weinstein JN, Guinney J, Saltz J, Holt RA, Rabkin CS et al (2019) The immune landscape of cancer. Immunity 51:411–412. https://doi.org/10.1016/j.immuni.2019.08.004

    Article  CAS  PubMed  Google Scholar 

  53. Jitariu AA, Cimpean AM, Kundnani NR, Raica M (2015) Platelet-derived growth factors induced lymphangiogenesis: evidence, unanswered questions and upcoming challenges. Arch Med Sci 11:57–66. https://doi.org/10.5114/aoms.2015.49217

    Article  PubMed  PubMed Central  Google Scholar 

  54. Onimaru M, Yonemitsu Y, Fujii T, Tanii M, Nakano T, Nakagawa K, Kohno R, Hasegawa M, Nishikawa S, Sueishi K (2009) VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol 297:H1685-1696. https://doi.org/10.1152/ajpheart.00015.2009

    Article  CAS  PubMed  Google Scholar 

  55. Kodama M, Kitadai Y, Sumida T, Ohnishi M, Ohara E, Tanaka M, Shinagawa K, Tanaka S, Yasui W, Chayama K (2010) Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor beta is associated with lymphatic metastasis in human gastric carcinoma. Cancer Sci 101:1984–1989. https://doi.org/10.1111/j.1349-7006.2010.01639.x

    Article  CAS  PubMed  Google Scholar 

  56. Donnem T, Al-Saad S, Al-Shibli K, Busund LT, Bremnes RM (2010) Co-expression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer. Ann Oncol 21:223–231. https://doi.org/10.1093/annonc/mdp296

    Article  CAS  PubMed  Google Scholar 

  57. Jansson S, Aaltonen K, Bendahl PO, Falck AK, Karlsson M, Pietras K, Ryden L (2018) The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res Treat 169:231–241. https://doi.org/10.1007/s10549-018-4664-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Feakins RM, Wells CA, Young KA, Sheaff MT (2000) Platelet-derived growth factor expression in phyllodes tumors and fibroadenomas of the breast. Hum Pathol 31:1214–1222. https://doi.org/10.1053/hupa.2000.18481

    Article  CAS  PubMed  Google Scholar 

  59. Li X, Warren S, Pelekanou V, Wali V, Cesano A, Liu M, Danaher P, Elliott N, Nahleh ZA, Hayes DF, Hortobagyi GN, Barlow WE, Hatzis C, Pusztai L (2019) Immune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial. J Immunother Cancer 7:88. https://doi.org/10.1186/s40425-019-0563-7

    Article  PubMed  PubMed Central  Google Scholar 

  60. Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, Seoane J (2007) High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11:147–160. https://doi.org/10.1016/j.ccr.2006.11.023

    Article  CAS  PubMed  Google Scholar 

  61. Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97:512–523. https://doi.org/10.1161/01.RES.0000182903.16652.d7

    Article  CAS  PubMed  Google Scholar 

  62. Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grunert S (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116:1561–1570. https://doi.org/10.1172/JCI24652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Thies KA, Hammer AM, Hildreth BE 3rd, Steck SA, Spehar JM, Kladney RD, Geisler JA, Das M, Russell LO, Bey JFt, Bolyard CM, Pilarski R, Trimboli AJ, Cuitino MC, Koivisto CS, Stover DG, Schoenfield L, Otero J, Godbout JP, Chakravarti A, Ringel MD, Ramaswamy B, Li Z, Kaur B, Leone G, Ostrowski MC, Sizemore ST, Sizemore GM (2021) Stromal platelet-derived growth factor receptor-beta signaling promotes breast cancer metastasis in the brain. Cancer Res 81:606–618. https://doi.org/10.1158/0008-5472.CAN-19-3731

    Article  CAS  PubMed  Google Scholar 

  64. Guo P, Hu B, Gu W, Xu L, Wang D, Huang HJ, Cavenee WK, Cheng SY (2003) Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 162:1083–1093. https://doi.org/10.1016/S0002-9440(10)63905-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219

    CAS  PubMed  Google Scholar 

  66. Czekierdowska S, Stachowicz N, Chrosciel M, Czekierdowski A (2017) Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B. Ginekol Pol 88:120–128. https://doi.org/10.5603/GP.a2017.0023

    Article  PubMed  Google Scholar 

  67. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215. https://doi.org/10.1016/j.devcel.2011.07.001

    Article  CAS  PubMed  Google Scholar 

  68. Satyananda V, Oshi M, Tokumaru Y, Maiti A, Hait N, Matsuyama R, Endo I, Takabe K (2021) Sphingosine 1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) and exported via ABCC1 is related to hepatocellular carcinoma (HCC) progression. Am J Cancer Res 11:4394–4407

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Tsuchida J, Nagahashi M, Nakajima M, Katsuta E, Rashid OM, Qi Q, Yan L, Okuda S, Takabe K, Wakai T (2020) Sphingosine kinase 1 is associated with immune cell-related gene expressions in human breast cancer. J Surg Res 256:645–656. https://doi.org/10.1016/j.jss.2020.06.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Takabe K, Spiegel S (2014) Export of sphingosine-1-phosphate and cancer progression. J Lipid Res 55:1839–1846. https://doi.org/10.1194/jlr.R046656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tsuchida J, Nagahashi M, Nakajima M, Moro K, Tatsuda K, Ramanathan R, Takabe K, Wakai T (2016) Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis. J Surg Res 205:85–94. https://doi.org/10.1016/j.jss.2016.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jitariu AA, Raica M, Cimpean AM, Suciu SC (2018) The role of PDGF-B/PDGFR-BETA axis in the normal development and carcinogenesis of the breast. Crit Rev Oncol Hematol 131:46–52. https://doi.org/10.1016/j.critrevonc.2018.08.002

    Article  PubMed  Google Scholar 

  73. Manzat Saplacan RM, Balacescu L, Gherman C, Chira RI, Craiu A, Mircea PA, Lisencu C, Balacescu O (2017) The role of PDGFs and PDGFRs in colorectal cancer. Mediators Inflamm 2017:4708076. https://doi.org/10.1155/2017/4708076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schoppmann SF, Alidzanovic L, Schultheis A, Perkmann T, Brostjan C, Birner P (2013) Thrombocytes correlate with lymphangiogenesis in human esophageal cancer and mediate growth of lymphatic endothelial cells in vitro. PLoS ONE 8:e66941. https://doi.org/10.1371/journal.pone.0066941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Forsberg K, Valyi-Nagy I, Heldin CH, Herlyn M, Westermark B (1993) Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci USA 90:393–397. https://doi.org/10.1073/pnas.90.2.393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Primac I, Maquoi E, Blacher S, Heljasvaara R, Van Deun J, Smeland HY, Canale A, Louis T, Stuhr L, Sounni NE, Cataldo D, Pihlajaniemi T, Pequeux C, De Wever O, Gullberg D, Noel A (2019) Stromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression. J Clin Invest 129:4609–4628. https://doi.org/10.1172/JCI125890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jennings MT, Hart CE, Commers PA, Whitlock JA, Martincic D, Maciunas RJ, Moots PL, Shehab TM (1997) Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor. J Neurooncol 31:233–254. https://doi.org/10.1023/a:1005767616500

    Article  CAS  PubMed  Google Scholar 

  78. Lebrun JJ (2012) The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012:381428. https://doi.org/10.5402/2012/381428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bronzert DA, Bates SE, Sheridan JP, Lindsey R, Valverius EM, Stampfer MR, Lippman ME, Dickson RB (1990) Transforming growth factor-beta induces platelet-derived growth factor (PDGF) messenger RNA and PDGF secretion while inhibiting growth in normal human mammary epithelial cells. Mol Endocrinol 4:981–989. https://doi.org/10.1210/mend-4-7-981

    Article  CAS  PubMed  Google Scholar 

  80. Kuzmanov A, Hopfer U, Marti P, Meyer-Schaller N, Yilmaz M, Christofori G (2014) LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling. Mol Oncol 8:401–416. https://doi.org/10.1016/j.molonc.2013.12.009

    Article  CAS  PubMed  Google Scholar 

  81. Lev DC, Kim SJ, Onn A, Stone V, Nam DH, Yazici S, Fidler IJ, Price JE (2005) Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin Cancer Res 11:306–314

    Article  CAS  Google Scholar 

  82. Yokoyama Y, Mori S, Hamada Y, Hieda M, Kawaguchi N, Shaker M, Tao Y, Yoshidome K, Tsujimoto M, Matsuura N (2011) Platelet-derived growth factor regulates breast cancer progression via beta-catenin expression. Pathobiology 78:253–260. https://doi.org/10.1159/000328061

    Article  CAS  PubMed  Google Scholar 

  83. Schito L, Rey S, Tafani M, Zhang H, Wong CC, Russo A, Russo MA, Semenza GL (2012) Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA 109:E2707-2716. https://doi.org/10.1073/pnas.1214019109

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wyss CB, Duffey N, Peyvandi S, Barras D, Martinez Usatorre A, Coquoz O, Romero P, Delorenzi M, Lorusso G, Ruegg C (2021) Gain of HIF1 activity and loss of miRNA let-7d promote breast cancer metastasis to the brain via the PDGF/PDGFR axis. Cancer Res 81:594–605. https://doi.org/10.1158/0008-5472.CAN-19-3560

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was supported by US National Institutes of Health (NIH) grant numbers R37CA248018, R01CA250412, R01CA251545, R01EB029596, as well as US Department of Defense BCRP grant number W81XWH-19–1-0674 and W81XWH-19–1-0111 to K.T. S.G. was supported by the National Center for Advancing Translational Sciences of the NIH grant numbers KL2TR001413 and UL1TR001412. National Cancer Institute, cancer center support grant P30CA016056 supports Roswell Park Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Rongrong Wu, Yoshihisa Tokumaru, Masanori Oshi & Kazuaki Takabe

  2. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan

    Rongrong Wu, Mariko Asaoka, Takashi Ishikawa & Kazuaki Takabe

  3. Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Shipra Gandhi

  4. Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, 501-1193, Japan

    Yoshihisa Tokumaru

  5. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan

    Masanori Oshi & Kazuaki Takabe

  6. Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Li Yan

  7. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, 14263, USA

    Kazuaki Takabe

  8. Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kazuaki Takabe

  9. Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan

    Kazuaki Takabe

Authors
  1. Rongrong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shipra Gandhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshihisa Tokumaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariko Asaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masanori Oshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuaki Takabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization—RW, TI, KT. Methodology—RW, KT. Formal analysis—RW. Original draft preparation—RW. Review and editing—RW, SG, YT, MA, MO, LY, TI, KT. Supervision—KT. Project administration—KT. Funding acquisition—KT.

Corresponding author

Correspondence to Kazuaki Takabe.

Ethics declarations

Conflict of interest

No conflicts of interest to disclose.

Ethical approval

Ethical review and approval were waived for this study, due to that all cohort information was de-identified and had passed ethical review at the initial publication.

Consent to publication

Patient consent was waived due to that all data were obtained from de-identified publicly available cohorts, and patient consent was obtained at the time of initial publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 11 KB)

Supplementary file2 (XLSX 12 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, R., Gandhi, S., Tokumaru, Y. et al. Intratumoral PDGFB gene predominantly expressed in endothelial cells is associated with angiogenesis and lymphangiogenesis, but not with metastasis in breast cancer. Breast Cancer Res Treat 195, 17–31 (2022). https://doi.org/10.1007/s10549-022-06661-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-022-06661-w

Keywords

Search

Navigation