ABSTRACT
BACKGROUND: In most patients with breast cancer, radiotherapy induces inflammation that is characterised by an increase of promigratory factors in healthy tissues surrounding the tumour. However, their role in the emergence of the migration phenotype and formation of metastases is still unclear. METHODS: A single mammary gland of BALB/c mice was irradiated with four doses of 6 Gy given at a 24-h interval. After the last session of irradiation, treated and control mammary glands were either collected for quantification of promigratory and proinflammatory factors or were implanted with fluorescent ubiquitination-based cell cycle indicator (FUCCI)-expressing mouse mammary cancer D2A1 cells. The migration of cancer cells in the mammary glands was monitored by optical imaging. On day 21, mammary tumours and lungs were collected for histology analyses and the quantification of metastases. RESULTS: Pre-irradiation of the mammary gland increased by 1.8-fold the migration of cancer cells, by 2-fold the quantity of circulating cancer cells and by 2.4-fold the number of lung metastases. These adverse effects were associated with the induction of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). CONCLUSION: The emergence of the metastasis phenotype is believed to be associated with the accumulation of mutations in cancer cells. Our results suggest an alternative mechanism based on promigratory factors from irradiated mammary glands. In clinic, the efficiency of radiotherapy could be improved by anti-inflammatory agents that would prevent the stimulation of cancer cell migration induced by radiation.
Subject(s)
Cell Movement/radiation effects , Lung Neoplasms/secondary , Mammary Glands, Animal/radiation effects , Mammary Neoplasms, Experimental/pathology , 3T3 Cells , Animals , Cell Line, Tumor , Cyclooxygenase 2/biosynthesis , Female , Interleukin-6/biosynthesis , Mammary Neoplasms, Experimental/metabolism , Mice , Mice, Inbred BALB C , Neoplastic Cells, CirculatingABSTRACT
BACKGROUND: Recent evidences support that radiation can promote the invasion of cancer cells. As interactions between cancer cells and surrounding stromal cells can have an important role in tumour progression, we determined whether an irradiation to fibroblasts can enhance the invasiveness of breast cancer cells. The role of cyclooxygenase-2 (COX-2), an inflammatory enzyme frequently induced by radiotherapy, was investigated. METHODS: Irradiated 3T3 fibroblasts were plated in the lower compartment of invasion chambers and used as chemoattractant for non-irradiated human breast cancer cell MDA-MB-231, which are oestrogen receptor negative (ER(-)) and the oestrogen receptor positive (ER(+)) MCF-7 cells. Stimulation of COX-2 expression in irradiated 3T3 cells was measured by a semi-quantitative qPCR and western blot. Capacity of the major product of COX-2, the prostaglandin E2 (PGE(2)), to stimulate the production of the matrix metalloproteinase-2 (MMP-2) and cancer cell invasion were assessed with a zymography gel and invasion chambers. RESULTS: Irradiation (5 Gy) of 3T3 fibroblasts increased COX-2 expression and enhanced by 5.8-fold the invasiveness of non-irradiated MDA-MB-231 cells, while their migration was not modified. Addition of the COX-2 inhibitor NS-398 completely prevented radiation-enhancement of cancer cell invasion. Further supporting the potential role of COX-2, addition of PGE(2) has increased cancer cell invasion and release of MMP-2 from the MDA-MB-231 cells. This effect of radiation was dependant on the expression of membrane type 1 (MT1)-MMP, which is required to activate the MMP-2, but was not associated with the ER status. Although irradiated fibroblasts stimulated the invasiveness of MDA-MB-231 ER(-) cells, no enhancement was measured with the ER(+) cell line MCF-7. CONCLUSIONS: Radiation-enhancement of breast cancer cell invasion induced by irradiated 3T3 fibroblasts is not dependant on the ER status, but rather the expression of MT1-MMP. This adverse effect of radiation can be prevented by a specific COX-2 inhibitor.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Fibroblasts , Matrix Metalloproteinase 2/metabolism , Blotting, Western , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/radiotherapy , Cell Line, Tumor , Cell Movement , Cyclooxygenase 2/genetics , Dinoprostone/metabolism , Female , Fibroblasts/radiation effects , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness , Polymerase Chain Reaction , Radiotherapy/adverse effectsABSTRACT
To assess the use of complementary tests by oncologists during staging and follow-up of breast cancer patients, a study was performed comparing actual procedures with current literature recommendations. A survey concerning the use of biochemical, radiological and radionuclide tests was presented to a sample of 58 radiation oncologists and medical oncologists involved in the treatment of breast cancer patients, with a 71% response rate. During the post-treatment surveillance, respectively 3%, 24%, 37%, 76% and 96% of the physicians scheduled liver scans, liver ultrasounds, bone scans, chest roentgenograms or mammograms on a regular basis. The frequency of use of various procedures are reported with a reference to the cost-benefit ratio, a matter of current interest. Although most oncologists limit their use of diagnostic tests, some still rely on extensive work-up to detect early recurrences or metastases, an approach that remains controversial in today's literature.
