title: PDGF-D improves drug delivery and efficacy via vascular normalization, but promotes lymphatic metastasis by activating CXCR4 in breast cancer.
abstract: OBJECTIVE
  Unlike platelet-derived growth factor-B (PDGF-B), the role of PDGF-D in tumor progression or treatment is largely unknown. To this end, we determined the role of PDGF-D in breast cancer progression, metastasis, and response to chemotherapy.
  
  
  METHODS
  We first examined PDGF-D expression in human breast carcinomas by immunohistochemical (IHC) staining. To mimic high PDGF-D expressing tumors, we stably transfected the breast cancer cell lines MDA-MB-231 and 4T1 with pdgf-d cDNA, and implanted these tumor cells orthtopically into nude mice. We monitored tumor growth by caliper measurement and bioluminescence imaging. We also used short hairpin RNA interference (shRNAi) and imatinib to block PDGF-D/PDGFRβ signaling. Finally, we studied the effect of PDGF-D on doxorubicin delivery and efficacy.
  
  
  RESULTS
  Human breast cancers express high levels of PDGF-D. Overexpression of PDGF-D promoted tumor growth and lymph node metastasis through increased proliferation, decreased apoptosis, and induction of CXCR4 expression. Blockade of CXCR4 signaling abolished PDGF-D-induced lymph node metastasis. Furthermore, overexpression of PDGF-D increased perivascular cell coverage and normalized tumor blood vessels. As a result, PDGF-D overexpression facilitated tissue penetration of doxorubicin and enhanced its treatment efficacy.
  
  
  CONCLUSIONS
  PDGF-D is highly expressed in human breast cancer and facilitates tumor growth and lymph node metastasis, making it a potential target in breast cancer. At the same time, PDGF-D increases drug delivery and hence improves the efficacy of chemotherapy through vessel normalization. Therefore, judicious use of PDGF-D/PDGFRβ blockers would be necessary to minimize the adverse effects on concomitantly administered cytotoxic therapies.
authors: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Jieqiong
authors: J
authors: Liu
authors: Shan
authors: S
authors: Liao
authors: Yuhui
authors: Y
authors: Huang
authors: Rekha
authors: R
authors: Samuel
authors: Tony
authors: T
authors: Shi
authors: Kamila
authors: K
authors: Naxerova
authors: Peigen
authors: P
authors: Huang
authors: Walid
authors: W
authors: Kamoun
authors: Rakesh K
authors: RK
authors: Jain
authors: Dai
authors: D
authors: Fukumura
authors: Lei
authors: L
authors: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D000068877:Imatinib Mesylate; D008207:Lymphatic Metastasis; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C527276:CXCR4 protein, human; D008222:Lymphokines; C427493:PDGFD protein, human; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D019718:Receptors, CXCR4; D004317:Doxorubicin; D000068877:Imatinib Mesylate