Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression.
Myofibroblastic invasion associated with malignant epithelial cells of endometrial cancer as well as other cancers is often found in the interstitium. To assess the myofibroblastic-epithelial interaction, frozen sections from a total of 10 endometrial cancers with or without invasive myofibroblasts were immunohistochemically examined. Interestingly, the invasive myofibroblasts adjacent to malignant epithelial cells showed frequently intensive positive staining of several growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor I, and epidermal growth factor, the cognate receptors such as Fetal liver kinase-1/Kinase Insert Domain-containing receptor/VEGF receptor-2, fms-like tyrosine kinase-1/VEGF receptor-1, and epidermal growth factor receptor, several cell cycle regulators such as cyclins and cyclin dependent kinases, and estrogen receptor alpha. Moreover, we indicated that the majority of the myofibroblasts as well as cancer epithelial cells are proliferating because of their positive staining of proliferating cell nuclear antigen and Ki-67. Furthermore, the myofibroblasts were also positive of hypoxia-inducible factor 1 alpha, which is a marker protein of hypoxia, probably followed by activation of VEGF-Flk-1 and VEGF-fms-like tyrosine kinase-1 signals, which could initiate angiogenesis. These findings suggest directly that the myofibroblasts might participate in the progression of tumor cells in terms of cancer cell growth stimulation and also activated initiation of angiogenesis.
Orimo
A
A
Department of Biochemistry, Saitama Medical School, 38 Moro-Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. aorimo@saitama-med.ac.jp
Tomioka
Y
Y
Shimizu
Y
Y
Sato
M
M
Oigawa
S
S
Kamata
K
K
Nogi
Y
Y
Inoue
S
S
Takahashi
M
M
Hata
T
T
Muramatsu
M
M
D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000032:analysis; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D047628:Estrogen Receptor alpha; D005260:Female; D006133:Growth Substances / Q000032:analysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D009130:Muscle, Smooth / Q000737:chemistry / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D017978:Receptors, Growth Factor / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors / Q000032:analysis; D040281:Vascular Endothelial Growth Factor Receptor-1
D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D006133:Growth Substances; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1