Tumor Associated Stromal Cells Play a Critical Role on the Outcome of the Oncolytic Efficacy of Conditionally Replicative Adenoviruses

Abstract

The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd) is still limited by the inefficient infection of the tumor mass. Since tumor growth is essentially the result of a continuous cross-talk between malignant and tumor-associated stromal cells, targeting both cell compartments may profoundly influence viral efficacy. Therefore, we developed SPARC promoter-based CRAds since the SPARC gene is expressed both in malignant cells and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes Simplex thymidine kinase gene (Ad-F512 and Ad(I)-F512-TK, respectively) exerted a lytic effect on a panel of human melanoma cells expressing SPARC; but they were completely attenuated in normal cells of different origins, including fresh melanocytes, regardless of whether cells expressed or not SPARC. Interestingly, both CRAds displayed cytotoxic activity on SPARC positive-transformed human microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were therapeutically effective on SPARC positive-human melanoma tumors growing in nude mice but exhibited restricted efficacy in the presence of co-administered HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced the oncolytic efficacy of Ad(I)-F512-TK on SPARC-negative MIA PaCa-2 pancreatic cancer cells in vivo. Moreover, conditioned media produced by stromal cells pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on pancreatic cancer cells, but not on melanoma cells. The whole data indicate that stromal cells might play an important role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.

A Novel CDC25B Promoter–Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models

“…The plates were incubated for 1 hour after which the absorbance of each well was read at a wavelength of 490 nm. All assays were performed in quadruplicate, and each assay was repeated at least twice (17).…”

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

“…132 These barriers also affect the therapeutic efficacy of viral or non-viral vectors, [133][134][135] although recent data from our group have shown that targeting stromal cells with a conditionally replicative adenoviral vector improved viral therapeutic efficacy. 136 As the tumor stroma is highly permissive for cell migration, 137 a cell therapy strategy using MSCs as vehicles for gene delivery is expected to overcome the problems related to tumor penetrability.…”

The chicken chorioallantoic membrane tumor assay as model for qualitative testing of oncolytic adenoviruses

“…3,4 The role of stromal cells appears to be of critical importance in the limited spread of adenoviral vectors. 29 Given that all these structures are present in CAM tumors, we hypothesized that this model would be useful to test the propagation of oncolytic adenoviral vectors. A single injection of wt HAdV-5 was able to induce necrosis at the center of the tumors 6 days post-infection.…”

“…Many transgenes used to arm adenoviral vectors are designed to modify the tissue architecture. For instance, vectors that degrade the extracellular matrix, 6,7,33 inhibit the angiogenesis [34][35][36][37] or target the stromal cells 29 have been constructed. The CAM model is probably relevant to study such vectors.…”