The combination of the antiviral agent cidofovir and anti-EGFR antibody cetuximab exerts an antiproliferative effect on HPV-positive cervical cancer cell lines' in-vitro and in-vivo xenografts.

Cervical carcinoma remains a leading cause of female mortality worldwide and over 90% of these tumors contain the human papillomavirus (HPV) genome. Cross-talk between the epidermal growth factor receptor and HPV has been reported and is implicated in tumor progression. The combination of the antiviral compound cidofovir (Cd) with the monoclonal antibody antiepidermal growth factor receptor cetuximab (Cx) was evaluated. HPV-positive (HeLa and Me180) and HPV-negative (C33A, H460 and A549) human cancer cell lines were incubated with Cd (1-10 µg/ml) and/or Cx (10 or 50 µg/ml). The antitumor effect of the combination was assessed in vitro using a clonogenic survival assay, cell cycle analysis, and phospho-H2AX level. Tumor growth delay was assayed in vivo using xenograft models. A pan-genomic analysis was carried out to identify the genes expressed differentially in untreated HeLa HPV-positive cells versus cells treated by the Cd-Cx combination. The Cd-Cx combination inhibited proliferation in all the cell lines tested. The association of Cd and Cx exerted a synergistic activity on HPV-positive but not on HPV-negative cell lines. The combination delayed tumor growth of HPV-positive tumors in vivo; however, no efficacy was reported on HPV-negative C33A xenografts nor on cell lines treated by single-drug therapy. The combination induced an S-phase arrest associated with an enhanced level of the double-strand break in Me180 and HeLa cell lines. Gene profiling assays showed a significant differential modulation of genes in HeLa cell lines treated with the combination involving the EGR-1 transcription factor. The current data support a synergistic antiproliferative action of the Cd-Cx combination on HPV-related cervical tumors.

Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling.

The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation.