Mantle cell lymphoma activation enhances bortezomib sensitivity

Abstract

IntroductionMantle cell lymphoma (MCL) is an aggressive, incurable B-cell malignancy that makes up 5% to 10% of non-Hodgkin lymphoma (NHL) cases. 1 Patients with MCL typically present with extensive lymph node involvement as well as extranodal dissemination within the spleen, bone marrow, and gastrointestinal tract. Treatment with conventional cytotoxic agents produces high initial response rates, but the outcome of patients with MCL remains among the poorest of all NHL subtypes with a median overall survival of 3 to 4 years. 2,3 Relapse after initial disease control suggests that a subset of cells can survive treatment and mediate tumor regrowth. In many cancers, specific populations of tumor cells with increased clonogenic potential have been identified and referred to as tumor initiating cells or cancer stem cells (CSCs). 4 Similar to normal adult stem cells, CSCs may be quiescent and resistant to a wide variety of cytotoxic agents. [5][6][7] However, few strategies have been developed to overcome CSC quiescence and chemoresistance.Normal B cells can be activated by antigen binding to the B-cell receptor as well as several antigen-independent processes. Toll-like receptors (TLRs) are innate immune receptors that recognize a diverse range of pathogen-derived microbial molecules, and several TLRs are expressed during normal B-cell development. 8,9 In humans TLR9 is expressed in B cells and plasmacytoid dendritic cells and recognizes unmethylated cytosine-phosphate-guanosine (CpG) motifs that mimic bacterial or viral DNA to induce cellular activation and differentiation. [10][11][12] TLR9 is also expressed in a wide variety of B-cell leukemias and lymphomas, but CpG oligonucleotides (ODNs) may have varying effects, depending on the specific malignancy. 10,[13][14][15][16] CpG ODNs have been clinically studied as agents to induce or augment antitumor immunity in several tumor types, including B-cell NHL. 17,18 Although these trials have shown limited benefit, CpG ODNs have been relatively well tolerated, suggesting that they may be safely combined with other antitumor agents. We studied the effects of CpG ODNs in MCL cells and found that they activate a minor population of relatively quiescent cells with increased clonogenic potential. Furthermore, CpG ODNs induce plasmacytic differentiation of MCL cells and enhance sensitivity to the proteosome inhibitor bortezomib. Cells were cultured in complete media consisting of RPMI 1640, 2mM L-glutamine, 50 U/mL penicillin, 50 g/mL streptomycin, and 10% fetal bovine serum. Clonogenic growth was evaluated by plating 1000 cells/mL in 1 mL of 1.2% methylcellulose, 30% fetal bovine serum, 1% bovine serum albumin, 10 Ϫ4 M 2-mercaptoethanol, and 2mM L-glutamine. Samples were plated in triplicate onto 35-mm 2 tissue culture dishes and incubated at 37°C and 5% CO 2 . Colonies consisting of more than 40 cells were scored between 7 and 10 days with an inverted microscope. Serial replating was performed by washing plates with complete media and resuspending cells in the original vol...

The Role of Human Aldehyde Dehydrogenase in Normal and Cancer Stem Cells

“…Importantly, unlike CSCs that have been identified in other malignancies, there have been no surface antigens identified that could isolate and enrich for MCLs and other mature pre-germinal center B cell malignant cells [65]. The ALDH + MCL cells were observed to be relatively quiescent and resistant to the standard chemotherapeutic agents used for MCL patients, including dexamethasone (anti-inflammatory steroid), etoposide (topoisomerase II inhibitor), and bortezomib (proteasome inhibitor).…”

“…Moreb, et al observed that pre-treatment of bone marrow cells with IL-1 and TNF-α for 6 to 20 hours resulted in an increase in ALDH1 mRNA and protein levels [105], and that this ultimately leads cellular protection against 4-HC [104]. Since then, it has been determined that high cytosolic ALDH1A1 or ALDH3A1 activity in normal cells [106,107], stem cells [44], and cancer stem cells [65,74] confers resistance to therapy in preclinical model systems. The majority of these studies focused on alkylating agents such as CP and other oxazaphosphorines [13-16, 45, 78, 87, 88, 100-104, 106-110].…”

“…Subsequent studies have shown that CD44 + CD24 -breast cancer cells display an increased expression of stem cell markers, the ability to self-renew, an enhanced capacity for in vitro mammosphere formation and invasion, expression of higher levels of anti-apoptotic proteins, and the ability to recapitulate a heterogeneous tumor population [51][52][53][54][55]. CSCs have also been identified in several other cancer types, including various forms of leukemias as well as solid tumors of the liver, pancreas, brain, colon, prostate, and other organs based on various surface antigens [51,[56][57][58][59][60][61][62][63][64][65] (Table 2).…”

Targeting hedgehog in hematologic malignancy

“…63 The existence of such a population has been conclusively demonstrated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), and there is accumulating evidence for their existence in other hematologic and solid tumors, such as myeloma, lymphoma, glioblastoma, breast, and prostate cancer. 16,18,[64][65][66][67] In these malignancies, CSCs are predominantly quiescent and therefore resistant to conventional therapeutic approaches. Failure to effectively target these cells results in residual low-level disease and the likelihood of future relapse.…”

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

“…The protective efects of ALDH for CSCs may also include the inhibition of downstream apoptosis-related pathways [18,23,24]. ALDH-positive CSCs have also demonstrated resistance to myriad chemotherapeutic agents such as anthracyclines and taxanes [25,26], two classes of drugs commonly used in OS treatment. ALDH-positive cancer cells develop this drug resistance in part because of their increased ability to metabolize certain drugs into their nontoxic byproducts [27].…”