Mantle cell lymphoma (MCL) is characterized by an early, widespread dissemination and residual disease after conventional treatment, but the mechanisms responsible for lymphoma cell motility and drug resistance are largely unknown. There is growing evidence suggesting that chemokine receptors and adhesion molecules are critical for malignant B-cell trafficking and homing to supportive tissue microenvironments, where they receive survival and drug resistance signals. Therefore, we examined chemokine receptor and adhesion molecule expression and function in MCL cells and their importance for migration and adhesion to marrow stromal cells (MSCs). We found that MCL cells display high levels of functional CXCR4 and CXCR5 chemokine receptors and VLA-4 adhesion molecules. We also report that MCL cells adhere and spontaneously migrate beneath MSCs in a CXCR4- and VLA-4-dependent fashion (pseudoemperipolesis). Moreover, we demonstrate that MSCs confer drug resistance to MCL cells, particularly to MCL cells that migrate beneath MSC. To target MCL-MSC interactions, we tested Plerixafor, a CXCR4 antagonist, and natalizumab, a VLA-4 antibody. Both agents blocked functional responses to the respective ligands and inhibited adhesive interactions between MCL cells and MSCs. These findings provide a rationale to further investigate the therapeutic potential of these drugs in MCL.
"In addition to its extensive physiological roles, CXCR4 has also been found to be expressed by various human cancers including breast, prostate, lung, colon and multiple myeloma 7-14, and has been suggested to be involved in the process of cancer cell metastasis 15, 16. The first report regarding CXCR4 role in metastasis was published by Muller et al. who showed that the metastasis of breast cancer cell line is dependent on CXCR4/CXCL12 axis 9. Since then, multiple publications have shown that CXCR4 can provide survival and proliferation signals to cancer cells, direct these cells to specific metastatic sites and provide some resistance to chemotherapy 4, 6, 13. "
[Show abstract][Hide abstract] ABSTRACT: CXCR4 was found to be expressed by many different types of human cancers and its expression has been correlated with tumor aggressiveness, poor prognosis and resistance to chemotherapy. CXCR4 was also shown to contribute to metastatic seeding of organs that express its ligand CXCL12 and support the survival of these cells. These findings suggest that CXCR4 is a potentially attractive therapeutic target, and several antagonists and antibodies for this receptor were developed and are under clinical evaluation. Quantifying CXCR4 expression non-invasively might aid in prognostication as a mean for personalized therapy and post treatment monitoring. Multiple attempts were done over the recent years to develop imaging agents for CXCR4 using different technologies including PET, SPECT, fluorescent and bioluminescence, and will be reviewed in this paper.
"Mantle cell lymphomas also express high levels of chemokine receptors CXCR4, CXCR5, and integrin α4β1. These receptors were shown to be critical in adhesion of lymphoma cells to bone marrow stromal cells and also in their resistance against fludarabine-induced apoptosis . Thus, CXCR4 inhibitors coupled with anti-α4β1 integrin antibodies were shown to abrogate both adhesion and chemoresistance of mantle cell lymphoma. "
[Show abstract][Hide abstract] ABSTRACT: Resistance to apoptosis and chemotherapy is a hallmark of cancer cells, and it is a critical factor in cancer recurrence and patient relapse. Extracellular matrix (ECM) via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy. Several studies over the last decade have demonstrated that ECM/integrin signaling provides a survival advantage to various cancer cell types against numerous chemotherapeutic drugs and against antibody therapy. In this paper, we will discuss the major findings on how ECM/integrin signaling protects tumor cells from drug-induced apoptosis. We will also discuss the potential role of ECM in malignant T-cell survival and in cancer stem cell resistance. Understanding how integrins and their signaling partners promote tumor cell survival and chemoresistance will likely lead to the development of new therapeutic strategies and agents for cancer treatment.
"As the disease advances to leukemic phase, drugs that may be effective for MCL cells in circulating blood may not be as effective when MCL cells are partly protected in the tumor microenvironment in tissues. The proliferative potential and molecular signatures of MCL cells are different when the cells in nutrient-rich blood environment are compared with tumor environments that are localized to bone marrow or lymph nodes with stroma, in turn requiring specific targeting strategies . The neighboring stroma cells secrete various growth factors to the local environment and directly support and simultaneously protect MCL cells from anticancer drugs [34–36]. "
[Show abstract][Hide abstract] ABSTRACT: Isolation and amplification of primary lymphoma cells in vitro setting is technically and biologically challenging task. To optimize culture environment and mimic in vivo conditions, lymphoma cell lines were used as a test case and were grown in 3-dimension (3D) using a novel 3D tissue culture polystyrene scaffold with neonatal stromal cells to represent a lymphoma microenvironment. In this model, the cell proliferation was enhanced more than 200-fold or 20,000% neoplastic surplus in 7 days when less than 1% lymphoma cells were cocultured with 100-fold excess of neonatal stroma cells, representing 3.2-fold higher proliferative rate than 2D coculture model. The lymphoma cells grew and aggregated to form clusters during 3D coculture and did not maintained the parental phenotype to grow in single-cell suspension. The cluster size was over 5-fold bigger in the 3D coculture by day 4 than 2D coculture system and contained less than 0.00001% of neonatal fibroblast trace. This preliminary data indicate that novel 3D scaffold geometry and coculturing environment can be customized to amplify primary cancer cells from blood or tissues related to hematological cancer and subsequently used for personalized drug screening procedures.
Journal of Tissue Engineering 09/2011; 2011:362326. DOI:10.4061/2011/362326
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