Tumor infiltration with Vα24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against CD1d + cells, the majority of human tumors are CD1d -. Therefore, the role of NKTs in cancer remains largely unknown. Here, we demonstrate that CD68 + tumor-associated monocytes/macrophages (TAMs) represented the majority of CD1d-expressing cells in primary human neuroblastomas. TAMs stimulated neuroblastoma growth in human cell lines and their xenografts in NOD/SCID mice via IL-6 production. Indeed, TAMs produced IL-6 in primary tumors and in the BM of patients with metastatic neuroblastoma. Gene expression analysis using TaqMan low-density arrays of 129 primary human neuroblastomas without MYCN amplification revealed that high-level expression of TAM-specific genes (CD14, CD16, IL6, IL6R, and TGFB1) was associated with poor 5-year event-free survival. While NKTs were not cytotoxic against neuroblastoma cells, they effectively killed monocytes pulsed with tumor cell lysate. The killing of monocytes was CD1d restricted because it was inhibited by a CD1d-specific mAb. Cotransfer of human monocytes and NKTs to tumor-bearing NOD/SCID mice decreased monocyte number at the tumor site and suppressed tumor growth compared with mice transferred with monocytes alone. Thus, killing of TAMs reveals what we believe to be a novel mechanism of NKT antitumor activity that relates to the disease outcome.

The bone and bone marrow are among the most frequent sites of cancer metastasis. It is estimated that 350,000 patients die with bone metastases annually in the US. The ability of tumor cells to colonize the bone marrow and invade the bone is the result of close interactions between tumor cells and the bone marrow microenvironment. In this article, we review the contribution of interleukin-6 (IL-6) produced in the bone marrow microenvironment to bone metastasis. This cytokine has a strong pro-tumorigenic activity due to its multiple effects on bone metabolism, tumor cell proliferation and survival, angiogenesis, and inflammation. These effects are mediated by several signaling pathways, in particular the Janus kinase/signal transducer and transcription activator (JAK/STAT-3), Ras/mitogen activated protein kinase (MAPK), and phosphoinositol-3 kinase (PI3K)–protein kinase B/Akt (PkB/Akt), which are activated by IL-6 and amplified in the presence of soluble IL-6 receptor (sIL-6R). Supporting the role of IL-6 in human cancer is the observation of elevated serum levels of IL-6 and sIL-6R in patients with bone metastasis and their association with a poor clinical outcome. Over the last decade several large (monoclonal antibodies) and small (inhibitors of IL-6 mediated signaling) molecules that inhibit IL-6 activity in preclinical models have been developed. Several of these inhibitors are now undergoing phase I and II clinical trials, which will determine their inclusion in the list of effective targeted agents in the fight against cancer.

Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells.

Drug resistance is a major cause of treatment failure in cancer. Here we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin-6 (IL-6) alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also Treg cells and non-myeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.

BackgroundThe global burden from cancer is rising, especially as low-income countries like Bangladesh observe rapid aging. So far, there are no comprehensive descriptions reporting diagnosed cancer group that include hematological malignancies in Bangladesh.MethodsThis was a multi-center hospital-based retrospective descriptive study of over 5000 confirmed hematological cancer cases in between January 2008 to December 2012. Morphological typing was carried out using the “French American British” classification system.ResultsA total of 5013 patients aged between 2 to 90 years had been diagnosed with malignant hematological disorders. A 69.2% were males (n = 3468) and 30.8% females (n = 1545), with a male to female ratio of 2.2:1. The overall median age at diagnosis was 42 years. Acute myeloid leukemia was most frequent (28.3%) with a median age of 35 years, followed by chronic myeloid leukemia with 18.2% (median age 40 years), non-Hodgkin lymphoma (16.9%; median age 48 years), acute lymphoblastic leukemia (14.1%; median age 27 years), multiple myeloma (10.5%; median age 55 years), myelodysplastic syndromes (4.5%; median age 57 years) and Hodgkin’s lymphoma (3.9%; median age 36 years). The least common was chronic lymphocytic leukemia (3.7%; median age 60 years). Below the age of 20 years, acute lymphoblastic leukemia was predominant (37.3%), followed by acute myeloid leukemia (34%). Chronic lymphocytic leukemia and multiple myeloma had mostly occurred among older patients, aged 50-over.ConclusionsFor the first time, our study presents the pattern and distribution of diagnosed hematological cancers in Bangladesh. It shows differences in population distributions as compared to other settings with possibly a lower presence of non-Hodgkin lymphoma. There might be under-reporting of affected women. Further studies are necessary on the epidemiology, genetics and potential environmental risk factors within this rapidly aging country.