Recruitment of CD34(+) fibroblasts in tumor-associated reactive stroma: the reactive microvasculature hypothesis.
Reactive stroma co-evolves with cancer, exhibiting tumor-promoting properties. It is also evident at sites of wound repair and fibrosis, playing a key role in tissue homeostasis. The specific cell types of origin and the spatial/temporal patterns of reactive stroma initiation are poorly understood. In this study, we evaluated human tumor tissue arrays by using multiple labeled, quantitative, spectral deconvolution microscopy. We report here a novel CD34/vimentin dual-positive reactive fibroblast that is observed in the cancer microenvironment of human breast, colon, lung, pancreas, thyroid, prostate, and astrocytoma. Recruitment of these cells occurred in xenograft tumors and Matrigel plugs in vivo and was also observed in stromal nodules associated with human benign prostatic hyperplasia. Because spatial and temporal data suggested the microvasculature as a common site of origin for these cells, we analyzed microvasculature fragments in organ culture. Interestingly, fibroblasts with identical phenotypic properties and markers expanded radially from microvasculature explants. We propose the concept of reactive microvasculature for the evolution of reactive stroma at sites of epithelial disruption common in both benign and malignant disorders. Data suggest that the reactive stroma response is conserved among tissues, in normal repair, and in different human cancers. A more clear understanding of the nature and origin of reactive stroma is needed to identify novel therapeutic targets in cancer and fibrosis.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Rebeca
R
San Martin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
David A
DA
Barron
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Jennifer A
JA
Tuxhorn
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Steven J
SJ
Ressler
Department of Urology, Vanderbilt University, School of Medicine, Nashville, Tennessee.
Simon W
SW
Hayward
Department of Pathology and Immunolog, Baylor College of Medicine, Houston, Texas.
Xiaoyun
X
Shen
Department of Pathology and Immunolog, Baylor College of Medicine, Houston, Texas.
Rodolfo
R
Laucirica
Department of Pathology and Immunolog, Baylor College of Medicine, Houston, Texas.
Thomas M
TM
Wheeler
Department of Pathology and Immunolog, Baylor College of Medicine, Houston, Texas.
Carolina
C
Gutierrez
Department of Pathology and Immunolog, Baylor College of Medicine, Houston, Texas.
Gustavo E
GE
Ayala
Department of Pathology and Laboratory Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas.
Michael
M
Ittmann
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Electronic address: drowley@bcm.edu.
David R
DR
Rowley
D000818:Animals; D018952:Antigens, CD34; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
D018952:Antigens, CD34