Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5‐fluorouracil

Abstract

We determined the effects of organ environment on the response of murine CT-26 colon carcinoma cells to 2 structurally and pharmacologically distinct chemotherapeutic agents. CT-26 cells were injected i.v. (to produce lung lesions), s.c., into the cecal wall, and into the spleen (to produce spleen and liver lesions). Doxorubicin (DXR) at 10 mg/kg, 5-fluorouracil (5-FU) at 20 mg/kg, or saline (control) was injected intravenously on different schedules after tumor-cell implantation. The in vivo responses of the tumors growing in the cecum, spleen, liver, lung and subcutis were compared. Colon carcinomas growing in the subcutis were most sensitive to DXR. Tumors growing in the spleen and cecum were most sensitive to 5-FU and less so to DXR. Tumors in the liver were highly resistant to both drugs, whereas experimental lung metastases were sensitive to 5-FU but resistant to DXR. The differential responses of the tumors to the drugs were not due to drug distribution. The level of protein-kinase-C activity was elevated in the spleen, liver and cecum tumors as compared with s.c. tumors and correlated with the in vivo DXR resistance of the tumor cells. This correlation suggested that organ environment may modulate the chemosensitivity of tumor cells, at least in part, by perturbing signal transduction pathways. Collectively, the data indicate that the organ environment has profound effects on the response of tumor cells to chemotherapy. A molecular understanding of this phenomenon should facilitate the design of more effective systemic chemotherapy for cancer metastases.

Therapeutic effect of α-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice

“…Studies have shown that response to chemotherapeutic agents varies depending on whether the tumor was ectopic or orthotopic. 25 The similarity between our in vivo mouse model and human HCC is reflected by the following observations. First, intra-hepatic metastases were found in our model.…”

A novel mouse model for segmental orthotopic colon cancer

“…The degree of invasion may be modulated by cell type and time postinoculation. While previous reports have described cecal wall tumor cell implantation in mice, 14,15 injection in those studies was likely external to the muscularis externa, in the serosal and subserosal layers. Additionally, the cecal wall, including the serosal and subserosal layers, is the thickest portion of the murine colon; thus, direct injection more distally in the colon would be difficult to achieve and has not been reported, to our knowledge.…”

Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt

“…The organ microenvironment influences the phenotype of tumor cells and is essential for optimal growth of tumors, as originally enunciated by Paget's seed-and-soil hypothesis and confirmed by others (24). We selected human NSCLC lines H460 and A549 because these cells rapidly form tumors after xenografting into nude mice and express receptors for BN/GRP subtypes, such as GRP-R, NMB-R, and BRS-3 (4).…”