Tumour budding is associated with hypoxia at the advancing front of colorectal cancer.
OBJECTIVE
The tumour budding ability to predict cancer progression is felt to be worthy of investigation with regard to its biological properties. This study was aimed at evaluating the role of hypoxia and microvascularization in the morphogenesis of tumour budding in colorectal carcinoma.


RESULTS
The immunohistochemical expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase IX in cancer cells and CD105 in carcinoma-induced microvascularization were assessed in 479 colorectal cancers. Furthermore, MET proto-oncogene, receptor tyrosine kinase (MET) gene amplification was searched using fluorescence in-situ hybridization (FISH). Carbonic anhydrase IX and HIF-1α overall scores differed significantly in low- compared to high-grade tumour budding cancers (P < 0.001), both in pT1 and in pT2-4 tumours. Intratumour analysis of budding foci showed a striking absence of carbonic anhydrase IX immunostain in detaching cells with respect to the surrounding microsectors. The mean microvessel density values were significantly higher in the low- compared to the high-grade tumour budding groups (P < 0.001). A similar copy number of MET gene was detected in the two groups.


CONCLUSIONS
Our study shows that tumour budding is associated with hypoxia induced by hypovascularization at the advancing front of colorectal cancer and that budding cells express a HIF-1α-mediated hypoxic tumour phenotype. MET gene amplification is not related to tumour budding morphogenesis.
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Alberto
A
Righi
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Ivana
I
Sarotto
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Laura
L
Casorzo
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Silvia
S
Cavalchini
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Elena
E
Frangipane
Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
Mauro
M
Risio
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000090063:Proto-Oncogene Mas
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas
HIF-1α; MET; carbonic anhydrase; colorectal cancer; hypoxia; microvessel density; tumour budding