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The impact of bone-marrow derived cells on tumor growth and metastasis after cytotoxic anti-cancer drug treatment

Final Report Summary - BMDCS IN CANCER (The impact of bone-marrow derived cells on tumour growth and metastasis after cytotoxic anti-cancer drug treatment)

Tumour angiogenesis - the formation of new blood vessels - is being formed by two distinct main mechanisms: the local sprouting of endothelial cells from pre-existing vessels, and a systemic mobilisation of bone marrow derived endothelial precursor cells (Circulating endothelial precursor cell (CEP)s) which home to active sites of angiogenesis. The latter, includes additional types of bone marrow cells (except for EPCs), which in different ways can promote tumour angiogenesis and subsequent tumour growth. These cells act as vessel adjacent 'accessory' cells in the tumour microenvironment promoting angiogenesis in a paracrine manner, or by directly incorporating into the vessel lumen. Our previous studies focused on EPCs in order to address several important questions in cancer biology and therapy. We first asked whether such cells can be targeted by antiangiogenic drugs - relatively new drugs which have been approved by the Food and Drug Administration (FDA) for the treatment of several malignancies causing 'tumour starvation' and subsequent tumour death. We found that these drugs can cause a significant drop in the levels of EPCs in the blood, and as such these cells can predict the optimal biological dose of the antiangiogenic drug tested. This became an important issue in clinical oncology, since such drugs are not administered at the maximum concentration tolerated by the patients, but in a more biological dose based on drug activity. In additional studies, we investigated the impact of EPCs on tumour angiogenesis immediately after treatment with different anti-cancer drugs. We found that following therapy with some chemotherapy drugs, levels of different types of bone marrow proangiogenic cells are rapidly and markedly induced in the peripheral blood. Such cells home to the treated tumour site, and help promoting angiogenesis and tumour re-growth. In such cases, the addition of an antiangiogenic drug which blocks the mobilisation of these cells, helped improving the therapy outcome by inhibiting the rebound angiogenesis found following these treatments. These results therefore suggested that antiangiogenic drugs can chemosensitise the tumours, leading to enhanced treatment outcome and delayed tumour relapse.

Some questions, however, still remain open with respect to the contribution of the bone marrow cells to tumour angiogenesis. What are the bone marrow cell types which affect tumour growth and angiogenesis following treatment with anti-cancer drugs? How do they act at the treated tumour microenvironment? What other effects may take place during the therapy? Is there increased metastasis following therapy which can be induced by bone marrow cells? These questions can significantly expand our understanding how anti-cancer drugs work, and uncover the interactions between host cells, especially from the bone marrow, and tumour cells. Closing the gap of knowledge may provide a suitable background to identify ways and targets which can block these protumourigenic processes.

We identified a number of cell types which are induced in response to a variety of cytotoxic and cytostatic drugs. We studied the mobilisation and recruitment of such cells in drug combination which are clinically relevant and treatment which are the standard of care for several malignancies including breast, lung and colon cancers. By way of example, we found that FOLFOX chemotherapy induced EPCs, and hemangiocytes levels in peripheral blood, but did not affect the levels of myeloid derived suppressor cells. On the other hand, a combination of gemcitabine and cisplatium therapy, which is one of the standard treatments for breast canrcinoma did not induce the mobilisation of any of these cells. Consequently, we showed that the addition of an antiangiogenic drug to therapy which does not affect bone marrow derived cells, it also did not improve therapy outcome. We also focused on various factors and cytokines which can promote bone marrow derived cell mobilisation. Granulocyte colony-stimulating factor (G-CSF) was one of the factors subsequently upregulated in the plasma of treated mice.

Exogenous addition of G-CSF promoted tumour growth and diminished the therapy outcome of paclitaxel chemotherapy. Since G-CSF is known to induce the mobilisation of various bone marrow derived cells, and therefore can promote tumour re-growth by increasing systemic angiogenesis, we searched for drugs which block the homing and recruitment of these cells to the treated tumour site, hence blocking the ability of such cells to promote tumour angiogenesis and subsequent tumour re-growth. We found that Mozobil, a CXCR4 antagonist, can improve the therapy outcome of chemotherapy by inhibiting systemic angiogenesis while minimising the myelosuppression effects of the cytotoxic drug. Overall, these results provide an important basis for further validating the preclinical studies in the clinical setting.

Over the last decade, one of the most significant developments in medical oncology has been the approval of antiangiogenic drug-based therapies for the treatment of several malignancies in advanced stage disease. Despite these successes, the relative modest clinical survival benefits gained in addition to the high costs of such drugs, raises a number of important questions regarding the use of targeted antiangiogenic therapies. Our results identified several ways in which we can improve the clinical outcome of chemotherapy drugs which they are combined with antiangiogenic drugs. We showed that not only the type of tumour is important for the efficacy of antiangiogenic drug, but also the drug combination in which the antiangiogenic drug is administered with. We also identified new possible targets which can block cytokines and growth factors promoting tumour growth and systemic angiogenesis by means of bone marrow derive cell mobilisation and colonisation of treated tumours. These studies may pave the way for the evaluation of such treatment strategies in the clinic.