title: Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma.
abstract: OBJECTIVE
  Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1(+) (VEGFR-1(+)) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68(+) hemangiogenic cells and alpha-smooth muscle actin(+) (alpha-SMA(+)) stromal cells correlates with neoangiogenesis and progression in human non-Hodgkin's lymphoma subtypes.
  
  
  METHODS
  Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, alpha-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia.
  
  
  RESULTS
  Compared with indolent lymphomas, there was a profound increase in recruitment of CD68(+) cells and VEGFR-1(+) neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68(+) cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68(+) cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in alpha-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34(+) microvessel density and lymphoma histologic subtype.
  
  
  CONCLUSIONS
  Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1(+)CD68(+)VEGF-A(+) cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas alpha-SMA(+) stromal vascular network may be differentially targeted in CLL/SLL.
authors.affiliation: Center for Lymphoma and Myeloma, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Ruan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.forename: Pouneh
authors.initials: P
authors.lastname: Kermani
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christos
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Morton
authors.initials: M
authors.lastname: Coleman
authors.forename: Barbara
authors.initials: B
authors.lastname: Hempstead
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D008224:Lymphoma, Follicular / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000199:Actins; D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C467484:VEGFA protein, human