Pre-conditioning cryosurgery: Cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system

Jing Jiang, Raghav Goel, Stephen Schmechel, Gregory Vercellotti, Colleen Forster, John Bischof

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4. h prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery.. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e., inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4. h and diminished over several days. Early events (4-24. h) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, pre-conditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.

Original languageEnglish (US)
Pages (from-to)280-288
Number of pages9
JournalCryobiology
Volume61
Issue number3
DOIs
StatePublished - Dec 2010

Bibliographical note

Funding Information:
Institute for Engineering in Medicine , University of Minnesota; NIH RO1 NCl CA07528 for financial support. BioNet histology and digital imaging facilities are supported by NIH P30 CA77598 and P50 CA101955.

Keywords

  • Caspase
  • Cryosurgery
  • NFκB
  • Prostate cancer
  • TNF-α

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