Treating cancer patients with metastatic disease remains an ultimate challenge inclinical oncology. Because invasive cancer precludes or limits the use of surgery,metastatic setting is often associated with (poor) survival, rather than sustainedremission, in patients with common cancers like lung, digestive or breast carcinomas.Mathematical modeling may help us better identify non detectable metastatic status to inturn optimize treatment for patients with metastatic disease. In this paper we present afamily of models for the metastatic growth. They are based on four principles : to be assimple as possible, involving the least possible number of parameters, the maininformations are obtained from the primary tumor and being able to recover the variety ofphenomena observed by the clinicians. Several simulations of therapeutic strategies arepresented illustrating possible applications of modeling to the clinic.

It is well established that patients with bone metastases get good pain relief from radiotherapy. The aim of treatment is to achieve maximum pain relief with minimum morbidity. Accuracy and reproducibility of the patient’s position are fundamental to the successful delivery of radiation therapy. It has been recognised for many years, that the accuracy of patient positioning will improve the success of radiation treatment. A previous study carried out in the department showed that the use of only a single tattoo for the set-up of palliative patients resulted in poor accuracy. The aim of this study was to assess if the addition of extra skin marks improved the set-up accuracy of palliative patients being treated for spine and bone metastases. A protocol was implemented detailing the extra skin marks to be used. Daily portal images were acquired and analysed retrospectively using anatomy matching. The results obtained were then compared with those of the previous study. The use of extra skin marks resulted in a total of 45% of images within 5 mm tolerance compared with 36% of images in patients treated with a single centre tattoo. Also, the number of images with deviations greater than 15 mm was reduced by more than 50% with the addition of extra skin marks. This study has shown that extra skin marks do increase the set-up accuracy in palliative patients treated for spine and bone metastases. Therefore, the practice of using extra skin marks has become standard protocol for all palliative patients within the department.

Epidemiological investigation and animal studies have shown that dietary n-3 PUFA prevent the development and progression of certain types of cancer. However, conflicting results have been reported by the few studies that focused on the effect of dietary n-3 PUFA on the development of metastases. In the present study, we investigated the metastatic dissemination of murine T lymphoma lines with different metastatic potential transplanted into mice fed a fish oil diet, compared with mice fed a maize oil diet. Transplantation of highly metastatic S11 cells into animals fed a fish oil diet induced a large lymphomatoid infiltration in the spleen, associated with an eight-fold increase in spleen weight, compared with normal animals on the same diet. In contrast, only a limited increase in spleen weight was found in animals transplanted with S11 cells while fed a maize oil diet. No significant increase in spleen weight was found in animals transplanted with low-metastatic 164T2 cells regardless of whether they were fed a fish oil or a maize oil diet. At the end of experiment, an overt cachexia was shown by animals fed a fish oil diet transplanted with S11 cells, but not by those transplanted with 164T2 cells. The particularly high pro-metastatic effect of dietary n-3 PUFA on S11 cells rules out the generalisation that dietary n-3 PUFA inhibit tumour growth and progression.

Both epidemiological and experimental studies indicate that dietary n-3 PUFA inhibit carcinogenesis and tumour growth. Metastatic diffusion has also been found to be affected in animals fed diets containing purified n-3 PUFA or fish oil. In the present study, we investigated whether the metastatic diffusion of a highly metastatic variant (F10-SR cells) isolated from the B16 melanoma F10 line was affected by feeding host animals a diet containing 5 % fish oil. In these animals, compared with those fed a diet containing 5 % maize oil, there was a reduced number of metastatic pulmonary colonies. The immunohistochemical analysis of appropriate markers revealed that the antimetastatic effect of dietary n-3 PUFA was not related to a reduction of proliferation, but rather to an enhanced apoptotic activity. The reduction of von Willebrand factor immunoreactivity found in pulmonary colonies of F10-SR cells grown in fish oil-fed animals indicates that a decrease of angiogenesis contributes to the antimetastatic effect of dietary n-3 PUFA. This conclusion stands in spite of the higher expression of vascular endothelial growth factor observed in pulmonary colonies grown in fish oil-fed animals.

Transgenic and knockout mouse models are extensively used to study the mechanisms of tumour formation. The availability of mouse models to study metastatic spread of tumours is although quite limited. S100A4(mts1), that belongs to the S100 family of Ca-binding proteins, has been shown to function as a metastasis-promoting protein. We generated strains of mice with modified expression of S100A4 in order to understand the mechanism by which S100A4 protein stimulates metastatic spread of the tumour cells. Transgenic mice over-expressing the S100A4 gene in the mammary gland were crossed with GRS/A mice, characterized by a high incidence of spontaneous non-metastatic mammary tumours. The resulting hybrid mice developed metastatic tumours. Transgenic mice with ubiquitous expression of S100A4 developed vascular tumours, hemangiomas and contained enhanced levels of the S100A4 protein in the blood. Based on these observations we demonstrated that extracellular S100A4 functions as an angiogenic factor. Study of tumour development in the S100A4 – deficient mouse model demonstrated key role of extracellular S100A4 in stimulation of tumour development and metastasis formation.