Cancer microenvironment, extracellular matrix, and adhesion molecules: the bitter taste of sugars in chronic lymphocytic leukemia

Extensive studies have highlighted the key role of the cancer microenvironment in the progression of malignancies. One of the major constituents of the microenvironment is the extracellular matrix (ECM), containing a variety of components, each exhibiting distinct biochemical and biophysical properties, associated bioactive molecules including growth factors and cytokines, and other interacting receptors. ECM molecules also affect some fundamental properties of cancer cells, including the gene expression profile, state of differentiation, cell motility, and drug resistance. Some major components of the ECM are based on macropolysaccharide chains like hyaluronan, sometimes linked to a core protein like heparin sulfate proteoglycans. Hyaluronan is a high molecular weight glycosaminoglycan composed of glucuronic acid and N-acetylglucosamine disaccharides, and is a major component of the bone marrow ECM produced by stromal and hematopoietic progenitor cells [1,2]. Two major receptors mediate interactions of cells with hyaluronan, CD44 and its splice variants, and the receptor for hyaluronan-mediated motility (RHAMM) [3,4]. It is apparent that hyaluronan and its receptors are key regulators of cancer cell physiology. In acute myeloblastic leukemia (AML), high levels of CD44 present on leukemic cells are essential for leukemia regeneration, illustrating the involvement of niche-dependent factors in leukemia renewal [5]. Hyaluronan, or its degradation products, may also affect tumor-associated processes, including microenvironmental stromal cell recruitment and angiogenesis [6].

Fundamental differences have recently been reported in the gene expression profiles of chronic lymphocytic leukemia (CLL) cells from different sites in the same patients. These data highlight the central role of the microenvironment in regulating gene expression, and subsequently the phenotype of CLL cells [7]. In this issue of Leukemia and Lymphoma, Herishanu et al. analyze the involvement of the principal hyaluronan receptor CD44 in signaling responses and survival of CLL cells [8]. They show that CD44 is more strongly expressed on the more aggressive immunoglobulin heavy chain variable gene (IGHV)-unmutated CLL cells than on normal B-cells or IGHV-mutated CLL cells. In this respect, engagement of CD44 may trigger signaling responses in a variety of cancer cells, influencing their migration patterns, proliferation, and survival [9]. In CLL cells, this resulted in homotypic aggregation, and activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways. These responses were followed by an increased expression of the MCL-1 protein after 24 h stimulation by anti-CD44 antibodies, but with no increase in MCL-1 mRNA [8]. These data are consistent with known translational and post-translation effects of PI3K/AKT and MAPK/ERK signaling. The engagement of CD44, or alternatively, adhesion of CLL cells to its natural ligand hyaluronan, resulted in increased cell survival generated by the hyaluronan/CD44 axis [8]. CD44 and its ligand hyaluronan confer cell adhesion-mediated drug resistance (CAM-DR) on multiple myeloma, AML, and other types of cancer [6,9,10], and have also been shown to protect CLL cells from fludarabine-induced apoptosis [8]. Blockers of PI3K/AKT and MAPK/ERK abrogated CD44-mediated increase of MCL-1, and obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44, and synergized with fludarabine to induce apoptosis of CLL cells, thereby providing evidence for the presence of a biochemical cascade of CD44–PI3K/AKT and MAPK/ERK–MCL-1 with its anti-apoptotic effects [8].

Therapeutic outcomes in CLL have improved significantly in the past decade with the introduction of purine analogs, immunotherapy, and chemo-immunotherapeutic regimens, which consistently achieve clinical remissions [11,12]. However, current therapies are reaching their maximum efficacy and can cause major toxicities including myelosuppression, opportunistic infections, and even secondary cancers. Because of this, the search for novel agents with less toxicity has intensified, particularly for older patients with CLL and comorbidities who have poor tolerance to established regimens. As a result of this new agents are very much in demand, and the potential of many novel agents is now being investigated robustly [13–15]. In this regard the identification of the CD44 signaling cascade adds yet another novel therapeutic target for future study in CLL [16,17]. Indeed it is clear that the face of CLL therapy is rapidly changing.

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