Peri-lesional hypoxia accelerates the outgrowth of hepatic colorectal micrometastases after laser-induced thermotherapy Free

1388

The majority of liver metastases originating from colorectal tumors are unresectable. A subgroup of these liver tumors can be treated with thermal destruction techniques like laser induced thermotherapy (LITT) or radiofrequency ablation (RFA). Although LITT and RFA procedures are curative in a minority of patients, local tumor recurrence is commonly observed. The aim of this study was to assess whether local tissue destruction affects the outgrowth of micrometastases in the transition zone (TZ) between ablated and healthy tissue. Furthermore, we evaluated the effect of local tissue destruction on microcirculatory blood flow, hypoxia, and Hypoxia Inducible Factor-1α (HIF-1α) expression in the TZ.

Micrometastases were induced by intrasplenic injection of 5x10e4 C26 colon carcinoma cells into the livers of syngenic BALB/c mice. Three days later, LITT was applied to the left liver lobe (540J). Over time we evaluated how LITT affected tumor growth, microcirculatory blood flow, tissue hypoxia, and HIF-1α expression in the TZ versus the healthy tissue (Reference zone, RZ). We found that the outgrowth of micrometastases in the TZ was stimulated over 4-fold when compared to that in the RZ. Accelerated tumor growth was associated with prolonged and profound microcirculatory disturbances, peri-necrotic hypoxia and stabilization of HIF-1α. Treatment with the HSP90 inhibitor 17-DMAG prevented HIF-1α stabilization and reduced tumor growth in the TZ by 30-50%.

Conclusion: Thermal destruction of liver tissue causes prolonged disturbances of the microcirculation, prolonged tissue hypoxia and HIF-1α stabilization in the transition zone between ablated and healthy tissue. We propose that these events contribute to the accelerated outgrowth of microscopic tumor residue surrounding the ablated region, and thus, to local recurrence. Compounds that target HIF-1α may be effective in reducing local recurrence following thermal destruction of liver tumors.