Bone Marrow Microenvironment and Tumor Progression

The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed

Vincristine-induced peripheral neuropathy in pediatric oncology: A randomized controlled trial comparing push injections with one-hour infusions (the vinca trial)

Vincristine (VCR) is a frequently used chemotherapeutic agent. However, it can lead to VCR-induced peripheral neuropathy (VIPN). In this study we investigated if one-hour infusions of VCR instead of push-injections reduces VIPN in pediatric oncology patients. We conducted a multicenter randomized controlled trial in which participants received all VCR administrations through push injections or one-hour infusions. VIPN was measured at baseline and 1–5 times during treatment using Common Terminology Criteria of Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score. Moreover, data on co-medication, such as azole antifungals, were collected. Overall, results showed no effect of administration duration on total CTCAE score or ped-mTNS score. However, total CTCAE score was significantly lower in patients receiving one-hour infusions concurrently treated with azole antifungal therapy (β = −1.58; p = 0.04). In conclusion, generally VCR administration through one-hour infusions does not lead to less VIPN compared to VC

Stromal matrix metalloproteinase-9 (MMP-9) promotes pericyte recruitment in neuroblastoma angiogenesis : a new role for matrix metalloproteinases

Neuroblastoma is a highly invasive neural crest derived cancer and the second most common solid tumor in children. Matrix metalloproteinases (MMPs) constitute a family of more than 26 endopeptidases that are able to proteolytically process a growing number of matrix and non-matrix substrates. MMPs are involved at different levels of tumor progression. MMP-2 and MMP-9 are overexpressed in more advanced stages of neuroblastoma. Although MMP-2 is produced by both tumor cells and stromal cells, MMP-9 is only secreted by stromal cells. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Treatment with Prinomastat, a synthetic inhibitor of MMPs, prolonged tumor bearing mice survival, did not affect formation of liver metastases but inhibited intravascular colonization of the lung by the tumor cells. Treatment with Prinomastat reduced neuroblastoma tumor vascularization with the presence of smaller vessels. We examined the contribution of MMP-9 to tumor angiogenesis in immunodeficient MMP-9 deficient mice. We demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, associated with a significant decrease in pericytes present along microvessels. Further investigations revealed that in neuroblastoma tumor, MMP-9 is predominantly expressed by bone marrow-derived leukocytes and that it promotes leukocytes infiltration into the tumor stroma. Taken together, the data show that in neuroblastoma, MMP-9 enhances bone marrow-derived cells infiltration into the tumor microenvironment where they positively contribute to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.Thèse de doctorat en sciences biomédicales (biologie cellulaire et moléculaire) (MED 3) -- UCL, 200

Hematological disorders and leukemia in children with Down syndrome.

Constitutional trisomy 21 inherent to Down syndrome (DS) is associated with several hematological disorders occurring at different ages. Neonates with DS may present with transient asymptomatic blood count abnormalities such as neutrophilia, thrombocytopenia and polycythemia. Within 1-2 months of life, 3-10% of DS infants develop transient myeloproliferative disease. Despite a spontaneous regression in most of the cases, TMD can be fatal or lead to the subsequent development of myeloid leukemia in 20% of DS children (DS ML). DS ML has clinical and biological features that define a unique entity with a high sensitivity to chemotherapy and a favorable outcome. Children with DS also have an increased risk of developing acute lymphoblastic leukemia (ALL) characterized by a more heterogeneous pattern of genetic findings and by a higher rate of treatment-related toxicities. These features highlight the role of trisomy 21 in leukemogenesis and confirm the need of specific and adapted therapeutic approach for DS children with leukemia

Microscopic Infiltration of Cryopreserved Ovarian Tissue in 2 Patients With Ewing Sarcoma.

We report the clinical history of 2 female patients with Ewing sarcoma and microscopic ovarian infiltration. In both cases, the initial workup found no metastasis. However, the examination of cryopreserved ovarian tissues revealed the presence of CD99 positive tumor cells with rearrangement of EWS gene confirmed by FISH. Both children were treated as patients with localized tumor and are currently in remission. These reports underline that, in Ewing sarcoma patients, retransplantation of cryopreserved ovarian tissue is not harmless and could lead to cancer relapse. These observations question also on the significance of ovarian dissemination on Ewing sarcoma prognosis and therapy

Fibroepithelial Polyp as a Rare Cause of Bronchial Obstruction in a Child.

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