Abstract
Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.
Highlights
Tumor removal remains the principal treatment modality in the management of solid tumors
Following complete DU145 xenograft excision recurrent tumors developed in four of eight animals. This model was representative of complete tumor excision and depicted recurrent tumor growth when microscopic foci of residual neoplasia are retained following excisional surgery
Several trials have revisited the concept that tumor removal, and the processes by which this is achieved, exert potentiating effects on residual neoplastic tissue [3, 7]
Summary
Tumor removal remains the principal treatment modality in the management of solid tumors. Patients frequently retain neoplasia in a micro- or macroscopic form This fact, coupled with the possibility that the process of tumor removal may potentiate tumor growth, has major implications for patients with residual disease. Greater 50% of patients undergoing colorectal tumor excision, harbor or shed circulating tumor cells either prior to or during the procedure [9, 10] These facts indicate that residual neoplasia occurs in a variety of forms and in a significant proportion of patients, following surgery for rectal neoplasia. Tumor cell proliferation is increased in local tumor recurrences following curative-intent excisional surgery [3, 7] This finding indicates that surgical treatment undertaken in a cancer patient could promote recurrent tumor growth [3, 7]. This overlap underscores a relationship between tumor removal and recurrent tumor growth
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