Abstract
Tumors may be maintained by subpopulations of cells possessing stem cell-like properties. We evaluated the stem cell-like and tumor-forming properties of side population (SP) and CD133+/ CD44+ cells in Granta 519, a human mantle cell lymphoma cell line. The in-vitro Cobblestone Area Forming Cell (CAFC) assay, designed to detect stem and progenitor cells, revealed that SP cells contained the greatest proportion of stem cell-like cells. The addition of Matrigel to CAFC assays of SP and non-SP cells both increased their respective stem cell frequencies in comparison to those cultures without Matrigel, and additionally resulted in observed stem cell frequencies which were the same between SP and non-SP cells. Contrary, Matrigel decreased the stem cell frequencies of CD133+/CD44+ or CD133-/CD44- cells. In-vivo assays revealed tumor formation from Matrigel-mixed SP and non-SP cells, and in one instance, occurred with as few as one Matrigel-mixed SP cell. Vehicle-mixed injections of SP and non-SP tumor cells resulted in tumor formation from SP cells only. Tumor formation did not occur from Matrigel nor hyaluronan (cellular substrate for CD44-expressing cells)-mixed populations of CD133+/CD44+ or CD133-/CD44- cells. These data demonstrate that Matrigel modulates a stem cell phenotype and promotes tumor formation from SP and non-SP cells. The tumor micro-environmental niche and tumor cell to micro-environmental interactions may be important future targets for novel chemotherapeutic agents.
Highlights
Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s Lymphoma, characterized by an aberrant proliferation of mature B lymphocytes in the mantle zones of lymphoid follicles
For the purpose of more closely mimicking the in-vivo environment, we evaluated the stem cell-like and tumor-forming capabilities of Granta side population (SP) and CD133+/CD44+ cells in the presence of microenvironmental components found in Matrigel
While numerous reports have documented the existence of rare sub-populations of tumor-initiating cells (TICs) in a variety of carcinomas, the majority of these studies have failed to consider the role of the microenvironment in modulating the stem cell-like and tumor-forming properties of such cells
Summary
Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s Lymphoma, characterized by an aberrant proliferation of mature B lymphocytes in the mantle zones of lymphoid follicles. The disease has an aggressive clinical course with a median patient survival of only 3 - 4 years following diagnosis [1,2]. This dismal outcome is due to the advanced stage of disease upon diagnosis with several extranodal sites typically involved including the spleen [3], bone marrow [4] and gastrointestinal tract [5]. Increasing evidence has pointed to the existence of subsets of tumor cells proposed to be responsible for tumor initiation and propagation.
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