Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma.
The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2Kd-Ecad). Three-dimensional human tissue constructs harboring either H-2Kd-Ecad-expressing or control II-4 cells (pBabe, H-2Kd-EcadDeltaC25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd-Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 gamma2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Function-blocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low- to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease.
Margulis
Alexander
A
Division of Cancer Biology and Tissue Engineering, Department of Oral and Maxillofacial Pathology, School of Dental Medicine, Tufts University, Boston, MA 02111, USA.
Zhang
Weitian
W
Alt-Holland
Addy
A
Pawagi
Sujata
S
Prabhu
Padmaja
P
Cao
Jian
J
Zucker
Stanley
S
Pfeiffer
Laurence
L
Garfield
Jacqueline
J
Fusenig
Norbert E
NE
Garlick
Jonathan A
JA
D000818:Animals; D015820:Cadherins / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000503:physiopathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D053556:Keratin-1; D007633:Keratins / Q000096:biosynthesis; D007797:Laminin / Q000096:biosynthesis; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology*; D046509:Tissue Culture Techniques
D015820:Cadherins; C491616:KRT1 protein, human; D053556:Keratin-1; C400567:LAMC2 protein, human; D007797:Laminin; D007633:Keratins; D020782:Matrix Metalloproteinases