Giga - Annual report 2015

Soluble factors regulated by epithelial-mesenchymal transition mediate tumour angiogenesis and myeloid cell

recruitment

Suarez-Carmona M, Bourcy M, Lesage J, Leroi N, Syne L, Blacher S, Hubert P, Erpicum C, Foidart JM, Delvenne P, Birembaut P, Noel

A, Polette M, Gilles C.

Journal of Pathology

2015;236:491-504

Epithelial-mesenchymal transition (EMT) programmes provide cancer cells with invasive and survival capacities that might favour

metastatic dissemination. Whilst signalling cascades triggering EMT have been extensively studied, the impact of EMT on the cross-

talk between tumour cells and the tumour microenvironment remains elusive. We aimed to identify EMT-regulated soluble factors

that facilitate the recruitment of host cells in the tumour. Our findings indicate that EMT phenotypes relate to the induction of a panel

of secreted mediators, namely IL-8, IL-6, sICAM-1, PAI-1 and GM-CSF, and implicate the EMT-transcription factor Snail as a regulator

of this process. We further show that EMT-derived soluble factors are pro-angiogenic in vivo (in the mouse ear sponge assay), ex vivo

(in the rat aortic ring assay) and in vitro (in a chemotaxis assay). Additionally, conditioned medium from EMT-positive cells stimulates

the recruitment of myeloid cells. In a bank of 40 triple-negative breast cancers, tumours presenting features of EMT were significant-

ly more angiogenic and infiltrated by a higher quantity of myeloid cells compared to tumours with little or no EMT. Taken together,

our results show that EMT programmes trigger the expression of soluble mediators in cancer cells that stimulate angiogenesis and

recruit myeloid cells in vivo, which might in turn favour cancer spread.

Carcinogenic hpv infection in the cervical squamo-columnar junction

Mirkovic J, Howitt BE, Roncarati P, Demoulin S, Suarez-Carmona M, Hubert P, McKeon FD, Xian W, Li A, Delvenne P, Crum CP, Herfs M.

Journal of Pathology

2015;236:265-271

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in

the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical

neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial

phases of neoplasia. This study was designed to (1) determine if normal-appearing SCJ cells contained evidence of carcinogenic

HPV infection and (2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and

SCJ cells were analysed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ

hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16(ink4), Ki67, and HPV L1 protein. In

22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from eight

of ten with visible SCJ cells, six of which were HPV16/18 DNA-positive. In five of these latter cases, the SCJ cells were positive for

p16(ink4) and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in microdissected SCJ cells. Early

squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16(ink4) immunoreactivity, elevated proliferative

index, and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected

by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny

with increased proliferation and p16(ink4) expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV

genotypes and what variables determine transition to high-grade SIL remain unresolved, but the common event appears to be a

vulnerable cell at the SCJ.

Laboratories

Laboratory of Tumor and Development Biology

AgnèsNoel,DidierCataldo,Jean-MichelFoidart

Metastases Research Laboratory

Vincent Castronovo, Akeila Bellahcene

Laboratory of Experimental Pathology

Philippe Delvenne

Laboratory of Molecular Angiogenesis

Ingrid Struman

Laboratory of Connective Tissues Biology

Alain Colige

Laboratory of Human Genetics

Vincent Bours

Laboratory of Cellular and Molecular Epigenetics

Luc Willems

People

44 Scientists

57 PhD Students

20 Technicians

39%

61%