Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery.
OBJECTIVE
To establish a causal relationship between the gene expression profiles of angiogenetic molecular markers, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1), in rectal cancer and the local responsiveness to neoadjuvant chemoradiotherapy and subsequent disease recurrence.


METHODS
We examined the pre-treatment tumour biopsies (n=40) obtained from patients with rectal adenocarcinoma (clinical International Union Against Cancer stage ll/III) who were scheduled to receive neoadjuvant 5-fluorouracil-based chemoradiotherapy for EGFR, VEGF and HIF-1 expression by quantitative real-time polymerase chain reaction.


RESULTS
Responders (patients with significant tumour regression, i.e. pathological grades 2/3) showed significantly lower VEGF, HIF-1 and EGFR gene expression levels than the non-responders (patients with insignificant tumour regression, i.e. pathological grades 0/1) in the pre-treatment tumour biopsies. The elevated expression level of each gene could predict patients with a low response to chemoradiation. During the median follow-up of all patients (41 months; 95% confidence interval 28-60 months), 6/40 (15%) developed disease recurrence. Although local responsiveness to neoadjuvant chemoradiotherapy was associated with neither local nor systemic disease recurrence, lymph node metastasis and an elevated VEGF gene expression level were independent predictors of systemic disease recurrence. The 3-year disease-free survival rates of the patients with lower VEGF or EGFR expression levels were significantly lower than those of patients with higher VEGF or EGFR expression levels.


CONCLUSIONS
Analysing VEGF expression levels in rectal cancer may be of benefit in estimating the effects of neoadjuvant chemoradiotherapy and in predicting systemic recurrence after rectal cancer surgery.
Toiyama
Y
Y
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Edobashi 2-174 Tsu, Mie 514-8507, Japan. ytoi0725@clin.medic.mie-u.ac.jp
Inoue
Y
Y
Saigusa
S
S
Okugawa
Y
Y
Yokoe
T
T
Tanaka
K
K
Miki
C
C
Kusunoki
M
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; D066246:ErbB Receptors; D005472:Fluorouracil