Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.
Somatostatin analogs (SSA) with their potent antisecretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine tumors, such as gastroenteropancreatic and acromegaly-associated growth hormone secreting pituitary tumors. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal control is not achieved in a sizeable proportion of these patients. The reasons for this incomplete response to SSA treatment are unclear. We have found that the tumor suppressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to determine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF-I and presence of tumor shrinkage). All tumors displayed ZAC1 immunoreactivity [weak (+; n = 15), moderate (++; n = 16) and strong (+++; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF-I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at diagnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shrinkage and hormone normalization.
Theodoropoulou
Marily
M
Department of Endocrinology, Max Planck Institute of Psychiatry, 80804 Munich, Germany. marily@mpipsykl.mpg.de
Tichomirowa
Maria A
MA
Sievers
Caroline
C
Yassouridis
Alexander
A
Arzberger
Thomas
T
Hougrand
Olivier
O
Deprez
Manuel
M
Daly
Adrian F
AF
Petrossians
Patrick
P
Pagotto
Uberto
U
Beckers
Albert
A
Stalla
Günter K
GK
D000172:Acromegaly / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000032:analysis*; D015331:Cohort Studies; D005260:Female; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010911:Pituitary Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D012189:Retrospective Studies; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014157:Transcription Factors / Q000032:analysis*; D025521:Tumor Suppressor Proteins / Q000032:analysis*
D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; D010456:Peptides, Cyclic; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C060347:lanreotide; D019382:Human Growth Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D015282:Octreotide