Skip to main content
SpringerLink
Log in

Targeting the TumorMicroenvironment for Enhancing Chemotherapy in HematologicMalignancies

  • Chapter
  • First Online:
Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures

Part of the book series: Cancer Growth and Progression ((CAGP,volume 13))

  • 1146 Accesses

Abstract

Mounting evidence now suggests that dynamic interactions between the cancer cell and its local and systemic microenvironment play a critical role in tumor development and that all of the clinical properties of a tumor, including response to therapy, depend heavily on the tumor stroma. We have much less understanding of the biology and genetics of stroma-tumor interactions than we do of tumor cells. Despite recent advances in the treatment of cancer, cancer still remains incurable, largely because of the emergence of drug-resistant tumor cells. Hematologic malignancies arise from defects in normal hematopoiesis and are often associated with aberrant expression of growth and survival factors, such as TGF-□, VEGF, bFGF, IL-6, and BAFF. These growth factors have also been shown to be involved in dysregulated apoptosis. Once a hematopoietic cell becomes malignant, these growth factors can be produced by both the tumor cell as well as by cells surrounding the tumor. These surrounding cells, such as bone marrow stromal cells, together with the extracellular matrix, cytokines and growth factors, and blood vessels, comprise the tumor microenvironment. This microenvironment provides a safe haven for the tumor cells to grow, and, following chemotherapeutic treatment, contributes the emergence of minimal residual disease (MRD), where a small number of drug resistant tumor cells survive cytotoxic stress. These drug resistant tumor cells, which often exhibit upregulation of anti-apoptotic pathways, are typically the cause of relapse of hematologic diseases. Thus, targeting these tumor cells along with the tumor microenvironment in which the tumor cells reside is vital in overcoming the devastating effects associated with hematologic malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ALL:

Acute lymphoblastic leukemia

AML:

Acute myelocytic leukemia

APRIL:

A proliferation-inducing ligand

BAFF:

B cell-activating factor of the tumor necrosis factor family

bFGF:

Basic fibroblast growth factor

BMSC:

Bone marrow stromal cell

CAM-DR:

Cell adhesion mediated drug resistance

CLL:

Chronic lymphocytic leukemia

CML:

Chronic myelocytic leukemia

ECM:

Extracellular matrix

EM-DR:

Environment mediated drug resistance

FADD:

Fas-associated via death domain

FLIP:

FADD-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein

FN:

Fibronectin

HDACi:

Histone deacetylase inhibitor

HSC:

Hematopoietic stem cell

HSP:

Heat shock protein

IL-6:

Interleukin-6

MAPK:

Mitogen-activated protein kinase

MRD:

Minimal residual disease

MM:

Multiple myeloma

NF-κB:

Nuclear factor-kappaB

NHL:

Non-Hodgkin’s lymphoma

STAT:

Signal transducers and activators of transcription

TGF-β:

Transforming growth factor-beta

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

References

  1. Adams J, Kauffman M (2004) Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22:304–311

    CAS  PubMed  Google Scholar 

  2. Alexandrow MG, Moses HL (1995) Transforming growth factor beta and cell cycle regulation. Cancer Res 55:1452–1457

    CAS  PubMed  Google Scholar 

  3. Amoroso SR, Huang N, Roberts AB, Potter M, Letterio JJ. (1998) Consistent loss of functional transforming growth factor beta receptor expression in murine plasmacytomas. Proc Natl Acad Sci USA 95:189–194

    CAS  PubMed  Google Scholar 

  4. Anderson KC (2003) The role of immunomodulatory drugs in multiple myeloma. Semin Hematol 40:23–32

    CAS  PubMed  Google Scholar 

  5. Bataille R, Barlogie B, Lu ZY, Rossi JF, Lavabre-Bertrand T, Beck T, Wijdenes J, Brochier J, Klein B (1995) Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 86:685–691

    CAS  PubMed  Google Scholar 

  6. Bellamy WT, Dalton WS, Gleason MC, Grogan TM, Trent JM (1991) Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res 51:995–1002

    CAS  PubMed  Google Scholar 

  7. Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R (2006) Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 24:937–944

    CAS  PubMed  Google Scholar 

  8. Bisping G, Leo R, Wenning D, Dankbar B, Padró T, Kropff M, Scheffold C, Kröger M, Mesters RM, Berdel WE, Kienast J (2003) Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood 101(7):2775–2783

    CAS  PubMed  Google Scholar 

  9. Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473

    CAS  PubMed  Google Scholar 

  10. Capocasale RJ, Lamb RJ, Vonderheid EC, Fox FE, Rook AH, Nowell PC, Moore JS (1995) Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc Natl Acad Sci USA 92:5501–5505

    CAS  PubMed  Google Scholar 

  11. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105–115

    CAS  PubMed  Google Scholar 

  12. Chen-Kiang S (1995) Regulation of terminal differentiation of human B-cells by IL-6. Curr Top Microbiol Immunol 194:189–198

    CAS  PubMed  Google Scholar 

  13. Chesi M, Brents LA, Ely SA, Bais C, Robbiani DF, Mesri EA, Kuehl WM, Bergsagel PL (2001) Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97:729–736

    CAS  PubMed  Google Scholar 

  14. Cheung WC, Van Ness B (2002) Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia 16:1182–1188

    CAS  PubMed  Google Scholar 

  15. Corazza F, Hermans C, Ferster A, Fondu P, Demulder A, Sariban E (2004) Bone marrow stroma damage induced by chemotherapy for acute lymphoblastic leukemia in children. Pediatr Res 55:152–158

    PubMed  Google Scholar 

  16. Cotter FE, Johnson P, Hall P, Pocock C, al Mahdi N, Cowell JK, Morgan G (1994) Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model. Oncogene 9:3049–3055

    CAS  PubMed  Google Scholar 

  17. Dalton WS (2003) The tumor microenvironment: focus on myeloma. Cancer Treat Rev 29(Suppl 1):11–19

    CAS  PubMed  Google Scholar 

  18. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS (1999) Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93:1658–1667

    CAS  PubMed  Google Scholar 

  19. Damiano JS, Hazlehurst LA, Dalton WS (2001) Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia 15:1232–1239

    CAS  PubMed  Google Scholar 

  20. Dankbar B, Padró T, Leo R, Feldmann B, Kropff M, Mesters RM, Serve H, Berdel WE, Kienast J (2000) Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 95(8):2630–2636

    CAS  PubMed  Google Scholar 

  21. de la Fuente MT, Casanova B, Garcia-Gila M, Silva A, Garcia-Pardo A (1999) Fibronectin interaction with alpha4beta1 integrin prevents apoptosis in B cell chronic lymphocytic leukemia: correlation with Bcl-2 and Bax. Leukemia 13:266–274

    PubMed  Google Scholar 

  22. DeCoteau JF, Knaus PI, Yankelev H, Reis MD, Lowsky R, Lodish HF, Kadin ME (1997) Loss of functional cell surface transforming growth factor beta (TGF-beta) type 1 receptor correlates with insensitivity to TGF-beta in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 94:5877–5881

    CAS  PubMed  Google Scholar 

  23. Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, Cox MC, Franchi A, Bruno A, Mazzone C, Panetta P, Suppo G, Masi M, Amadori S (2003) Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 101:2125–2131

    PubMed  Google Scholar 

  24. Dias S, Choy M, Alitalo K, Rafii S (2002) Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 99:2179–2184

    CAS  PubMed  Google Scholar 

  25. Dias S, Shmelkov SV, Lam G, Rafii S (2002) VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 99:2532–2540

    CAS  PubMed  Google Scholar 

  26. Do RK, Hatada E, Lee H, Tourigny MR, Hilbert D, Chen-Kiang S (2000) Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med 192:953–964

    CAS  PubMed  Google Scholar 

  27. Dong M, Blobe GC (2006) Role of transforming growth factor-beta in hematologic malignancies. Blood 107:4589–4596

    CAS  PubMed  Google Scholar 

  28. Durand RE, Sutherland RM (1972) Effects of intercellular contact on repair of radiation damage. Exp Cell Res 71:75–80

    CAS  PubMed  Google Scholar 

  29. Espinoza-Hernandez L, Cruz-Rico J, Benitez-Aranda H, Martinez-Jaramillo G, Rodriguez-Zepeda MC, Velez-Ruelas MA, Mayani H (2001) In vitro characterization of the hematopoietic system in pediatric patients with acute lymphoblastic leukemia. Leuk Res 25:295–303

    CAS  PubMed  Google Scholar 

  30. Fernandez T, Amoroso S, Sharpe S, Jones GM, Bliskovski V, Kovalchuk A, Wakefield LM, Kim SJ, Potter M, Letterio JJ (2002) Disruption of transforming growth factor beta signaling by a novel ligand-dependent mechanism. J Exp Med 195:1247–1255

    CAS  PubMed  Google Scholar 

  31. Ferrajoli A, Faderl S, Ravandi F, Estrov Z (2006) The JAK-STAT pathway: a therapeutic target in hematological malignancies. Curr Cancer Drug Targets 6:671–679

    CAS  PubMed  Google Scholar 

  32. Fortney JE, Zhao W, Wenger SL, Gibson LF (2001) Bone marrow stromal cells regulate caspase 3 activity in leukemic cells during chemotherapy. Leuk Res 25:901–907

    CAS  PubMed  Google Scholar 

  33. Fragoso R, Pereira T, Wu Y, Zhu Z, Cabecadas J, Dias S (2006) VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood 107:1608–616

    CAS  PubMed  Google Scholar 

  34. Frassanito MA, Cusmai A, Iodice G, Dammacco F (2001) Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 97:483–489

    CAS  PubMed  Google Scholar 

  35. Gabrilove JL (2001) Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies. Oncologist 6(Suppl 5):4–7

    CAS  PubMed  Google Scholar 

  36. Garrido SM, Appelbaum FR, Willman CL, Banker DE (2001) Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Exp Hematol 29:448–457

    CAS  PubMed  Google Scholar 

  37. Geitz H, Handt S, Zwingenberger K (1996) Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 31:213–221

    CAS  PubMed  Google Scholar 

  38. Gery S, Koeffler HP (2007) Transcription factors in hematopoietic malignancies. Curr Opin Genet Dev 17:78–83

    CAS  PubMed  Google Scholar 

  39. Glasgow E, Mishra L (2008) Transforming growth factor-{beta} signaling and ubiquitinators in cancer. Endocr Relat Cancer 15:59–72

    CAS  PubMed  Google Scholar 

  40. Golay J, Cuppini L, Leoni F, Mico C, Barbui V, Domenghini M, Lombardi L, Neri A, Barbui AM, Salvi A, Pozzi P, Porro G, Pagani P, Fossati G, Mascagni P, Introna M, Rambaldi A (2007) The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells. Leukemia 21:1892–1900

    CAS  PubMed  Google Scholar 

  41. Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, Rixon M, Schou O, Foley KP, Haugen H, McMillen S, Waggie K, Schreckhise RW, Shoemaker K, Vu T, Moore M, Grossman A, Clegg CH (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302

    CAS  PubMed  Google Scholar 

  42. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH (2000) TACI, BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999

    CAS  PubMed  Google Scholar 

  43. Guasparri I, Keller SA, Cesarman E (2004) KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199:993–1003

    CAS  PubMed  Google Scholar 

  44. Guinness ME, Kenney JL, Reiss M, Lacy J (2000) Bcl-2 antisense oligodeoxynucleotide therapy of Epstein-Barr virus-associated lymphoproliferative disease in severe combined immunodeficient mice. Cancer Res 60:5354–5358

    CAS  PubMed  Google Scholar 

  45. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, Lin B, Lentzsch S, Davies FE, Chauhan D, Schlossman RL, Richardson P, Ralph P, Wu L, Payvandi F, Muller G, Stirling DI, Anderson KC (2001) Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 15:1950–1961

    CAS  PubMed  Google Scholar 

  46. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    CAS  PubMed  Google Scholar 

  47. Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R, Epstein J (1993) Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. Blood 81:3357–3364

    CAS  PubMed  Google Scholar 

  48. Hatada EN, Do RK, Orlofsky A, Liou HC, Prystowsky M, MacLennan IC, Caamano J, Chen-Kiang S (2003) NF-kappa B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-kappa B2 p100 to p52 in quiescent mature B cells. J Immunol 171:761–768

    CAS  PubMed  Google Scholar 

  49. Hayashi T, Hideshima T, Nguyen AN, Munoz O, Podar K, Hamasaki M, Ishitsuka K, Yasui H, Richardson P, Chakravarty S, Murphy A, Chauhan D, Higgins LS, Anderson KC (2004) Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin Cancer Res 10:7540–7546

    CAS  PubMed  Google Scholar 

  50. Hazlehurst LA, Argilagos RF, Dalton WS (2007) Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells. Br J Haematol 136:269–275

    CAS  PubMed  Google Scholar 

  51. Hazlehurst LA, Argilagos RF, Emmons M, Boulware D, Beam CA, Sullivan DM, Dalton WS (2006) Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. Cancer Res 66:2338–2345

    CAS  PubMed  Google Scholar 

  52. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19:4319–4327

    CAS  PubMed  Google Scholar 

  53. Hazlehurst LA, Enkemann SA, Beam CA, Argilagos RF, Painter J, Shain KH, Saporta S, Boulware D, Moscinski L, Alsina M, Dalton WS (2003) Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res 63:7900–7906

    CAS  PubMed  Google Scholar 

  54. Hazlehurst LA, Foley NE, Gleason-Guzman MC, Hacker MP, Cress AE, Greenberger LW, De Jong MC, Dalton WS (1999) Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res 59:1021–1028

    CAS  PubMed  Google Scholar 

  55. Hazlehurst LA, Landowski TH, Dalton WS (2003) Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 22:7396–7402

    CAS  PubMed  Google Scholar 

  56. Hazlehurst LA, Valkov N, Wisner L, Storey JA, Boulware D, Sullivan DM, Dalton WS (2001) Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 98:1897–1903

    CAS  PubMed  Google Scholar 

  57. He B, Chadburn A, Jou E, Schattner EJ, Knowles DM, Cerutti A (2004) Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS, APRIL. J Immunol 172:3268–3279

    CAS  PubMed  Google Scholar 

  58. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C (1999) NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. Embo J 18:4766–4778

    CAS  PubMed  Google Scholar 

  59. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076

    CAS  PubMed  Google Scholar 

  60. Horning SJ (1994) Treatment approaches to the low-grade lymphomas. Blood 83:881–884

    CAS  PubMed  Google Scholar 

  61. Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R (2002) Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood 99:3742–3747

    CAS  PubMed  Google Scholar 

  62. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H (2001) Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis. Oncogene 20:88–96

    CAS  PubMed  Google Scholar 

  63. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172

    CAS  PubMed  Google Scholar 

  64. Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B (2002) Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99:3398–3403

    CAS  PubMed  Google Scholar 

  65. Kaminska B, Wesolowska A, Danilkiewicz M (2005) TGF beta signalling and its role in tumour pathogenesis. Acta Biochim Pol 52:329–337

    CAS  PubMed  Google Scholar 

  66. Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C, Qian D, Morris L, Tidwell M, Chen H, Zwiebel J (2004) Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 10:3577–3585

    CAS  PubMed  Google Scholar 

  67. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, et al (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83–85

    CAS  PubMed  Google Scholar 

  68. Kern C, Cornuel JF, Billard C, Tang R, Rouillard D, Stenou V, Defrance T, Ajchenbaum-Cymbalista F, Simonin PY, Feldblum S, Kolb JP (2004) Involvement of BAFF, APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 103:679–688

    CAS  PubMed  Google Scholar 

  69. Khan SB, Maududi T, Barton K, Ayers J, Alkan S (2004) Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma. Br J Haematol 125:156–161

    CAS  PubMed  Google Scholar 

  70. Khare SD, Sarosi I, Xia XZ, McCabe S, Miner K, Solovyev I, Hawkins N, Kelley M, Chang D, Van G, Ross L, Delaney J, Wang L, Lacey D, Boyle WJ, Hsu H (2000) Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 97:3370–3375

    CAS  PubMed  Google Scholar 

  71. Kim R, Emi M, Tanabe K, Toge T (2004) Therapeutic potential of antisense Bcl-2 as a chemosensitizer for cancer therapy. Cancer 101:2491–2502

    CAS  PubMed  Google Scholar 

  72. Klasa RJ, Bally MB, Ng R, Goldie JH, Gascoyne RD, Wong FM (2000) Eradication of human non-Hodgkin’s lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide. Clin Cancer Res 6:2492–2500

    CAS  PubMed  Google Scholar 

  73. Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R (1989) Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73:517–526

    CAS  PubMed  Google Scholar 

  74. Klein B, Zhang XG, Lu ZY, Bataille R (1995) Interleukin-6 in human multiple myeloma. Blood 85:863–872

    CAS  PubMed  Google Scholar 

  75. Klener P Jr, Andera L, Klener P, Necas E, Zivny J (2006) Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of therapeutic approaches. Folia Biol (Praha) 52:119–136

    Google Scholar 

  76. Kline MP, Rajkumar SV, Timm MM, Kimlinger TK, Haug JL, Lust JA, Greipp PR, Kumar S (2007) ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia 21:1549–1560

    CAS  PubMed  Google Scholar 

  77. Konig A, Menzel T, Lynen S, Wrazel L, Rosen A, Al-Katib A, Raveche E, Gabrilove JL (1997) Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia 11:258–265

    CAS  PubMed  Google Scholar 

  78. Kuroda H, Matsunaga T, Terui T, Tanaka I, Takimoto R, Fujikawa K, Takayama T, Kato J, Hirayama Y, Sakamaki S, Kohda K, Niitsu Y (2004) Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-beta1. Br J Haematol 124:211–220

    CAS  PubMed  Google Scholar 

  79. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P (1998) Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 91:2387–2396

    CAS  PubMed  Google Scholar 

  80. Lagneaux L, Delforge A, Bron D, Massy M, Bernier M, Stryckmans P (1997) Heterogenous response of B lymphocytes to transforming growth factor-beta in B-cell chronic lymphocytic leukaemia: correlation with the expression of TGF-beta receptors. Br J Haematol 97:612–620

    CAS  PubMed  Google Scholar 

  81. Li ZW, Dalton WS (2006) Tumor microenvironment and drug resistance in hematologic malignancies. Blood Rev 20:333–342

    PubMed  Google Scholar 

  82. Liou HC, Nolan GP, Ghosh S, Fujita T, Baltimore D (1992) The NF-kappa B p50 precursor, p105, contains an internal I kappa B-like inhibitor that preferentially inhibits p50. Embo J 11:3003–3009

    CAS  PubMed  Google Scholar 

  83. Lwin T, Hazlehurst LA, Dessureault S, Lai R, Bai W, Sotomayor E, Moscinski LC, Dalton WS, Tao J (2007) Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood 110:1631–1638

    CAS  PubMed  Google Scholar 

  84. Lwin T, Hazlehurst LA, Li Z, Dessureault S, Sotomayor E, Moscinski LC, Dalton WS, Tao J (2007) Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia 21:1521–1531

    CAS  PubMed  Google Scholar 

  85. Lwin T, Crespo L, Wu A, Dessureault S, Shu H, Sotomayor E, Moscinski LC, Dalton WS, Tao J (2009) Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family (BAFF) in bone marrow stromal cells protects non-Hodgkin’s B lymphoma cells from apoptosis. Leukemia 23(1):170–177

    CAS  PubMed  Google Scholar 

  86. MacDonald I, Wang H, Grand R, Armitage RJ, Fanslow WC, Gregory CD, Gordon J (1996) Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines. Blood 87:1147–1154

    CAS  PubMed  Google Scholar 

  87. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL (1999) Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190:1697–1710

    CAS  PubMed  Google Scholar 

  88. Matter ML, Ruoslahti E (2001) A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription. J Biol Chem 276:27757–27763

    CAS  PubMed  Google Scholar 

  89. Meads MB, Gatenby RA, Dalton WS (2009). Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9(9):665–674. Epub 2009

    CAS  PubMed  Google Scholar 

  90. Menzel T, Rahman Z, Calleja E, White K, Wilson EL, Wieder R, Gabrilove J (1996) Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 87:1056–1063

    CAS  PubMed  Google Scholar 

  91. Mercurio F, DiDonato JA, Rosette C, Karin M (1993) p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev 7:705–718

    CAS  PubMed  Google Scholar 

  92. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, Munshi NC, Treon SP, Anderson KC (2002) Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99:4525–4530

    CAS  PubMed  Google Scholar 

  93. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380

    CAS  PubMed  Google Scholar 

  94. Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S (1997) BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood 90:1168–1174

    CAS  PubMed  Google Scholar 

  95. Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, Moine P, Rossi JF, Klein B, Tarte K (2004) BAFF, APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 103:3148–3157

    CAS  PubMed  Google Scholar 

  96. Mori N, Matsuda T, Tadano M, Kinjo T, Yamada Y, Tsukasaki K, Ikeda S, Yamasaki Y, Tanaka Y, Ohta T, Iwamasa T, Tomonaga M, Yamamoto N (2004) Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. J Virol 78:4582–4590

    CAS  PubMed  Google Scholar 

  97. Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ, Mundy GR, Yoneda T (2004) Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 104:2149–2154

    CAS  PubMed  Google Scholar 

  98. Moshaver B, van der Pol MA, Westra AH, Ossenkoppele GJ, Zweegman S, Schuurhuis GJ (2008) Chemotherapeutic treatment of bone marrow stromal cells strongly affects their protective effect on acute myeloid leukemia cell survival. Leuk Lymphoma 49:134–148

    CAS  PubMed  Google Scholar 

  99. Mudry RE, Fortney JE, York T, Hall BM, Gibson LF (2000) Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 96:1926–1932

    CAS  PubMed  Google Scholar 

  100. Naumann M, Wulczyn FG, Scheidereit C (1993) The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B. Embo J 12:213–222

    CAS  PubMed  Google Scholar 

  101. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI (2004) Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103:3503–3510

    CAS  PubMed  Google Scholar 

  102. Niu G, Shain KH, Huang M, Ravi R, Bedi A, Dalton WS, Jove R, Yu H (2001) Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res 61:3276–3280

    CAS  PubMed  Google Scholar 

  103. O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR (2007) Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25:1114–1120

    PubMed  Google Scholar 

  104. Ong YL, McMullin MF, Bailie KE, Lappin TR, Jones FG, Irvine AE (2000) High bax expression is a good prognostic indicator in acute myeloid leukaemia. Br J Haematol 111:182–189

    CAS  PubMed  Google Scholar 

  105. Pangalis GA, Kyrtsonis MC, Vassilakopoulos TP, Dimopoulou MN, Siakantaris MP, Emmanouilides C, Doufexis D, Sahanas S, Kontopidou FN, Kalpadakis C, Angelopoulou MK, Dimitriadou EM, Kokoris SI, Panayiotidis P (2006) Immunotherapeutic and immunoregulatory drugs in haematologic malignancies. Curr Top Med Chem 6:1657–1686

    CAS  PubMed  Google Scholar 

  106. Parry TJ, Riccobene TA, Strawn SJ, Williams R, Daoud R, Carrell J, Sosnovtseva S, Miceli RC, Poortman CM, Sekut L, Li Y, Fikes J, Sung C (2001) Pharmacokinetics and immunological effects of exogenously administered recombinant human B lymphocyte stimulator (BLyS) in mice. J Pharmacol Exp Ther 296:396–404

    CAS  PubMed  Google Scholar 

  107. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC (2001) Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 98:428–435

    CAS  PubMed  Google Scholar 

  108. Reed JC, Pellecchia M (2005) Apoptosis-based therapies for hematologic malignancies. Blood 106:408–418

    CAS  PubMed  Google Scholar 

  109. Rosato RR, Almenara JA, Grant S (2003) The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 63:3637–3645

    CAS  PubMed  Google Scholar 

  110. Ruscetti FW, Akel S, Bartelmez SH (2005) Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 24:5751–5763

    CAS  PubMed  Google Scholar 

  111. Salmeron A, Janzen J, Soneji Y, Bump N, Kamens J, Allen H, Ley SC (2001) Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem 276:22215–22222

    CAS  PubMed  Google Scholar 

  112. Salven P, Orpana A, Teerenhovi L, Joensuu H (2000) Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF, bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood 96:3712–3718

    CAS  PubMed  Google Scholar 

  113. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111–2114

    CAS  PubMed  Google Scholar 

  114. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnely SC, Strieter R, Haslett C (1999) Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 5:662–668

    CAS  PubMed  Google Scholar 

  115. Settles B, Stevenson A, Wilson K, Mack C, Ezell T, Davis MF, Taylor LD (2001) Down-regulation of cell adhesion molecules LFA-1 and ICAM-1 after in vitro treatment with the anti-TNF-alpha agent thalidomide. Cell Mol Biol (Noisy-le-grand) 47:1105–1114

    CAS  Google Scholar 

  116. Shain KH, Landowski TH, Dalton WS (2002) Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J Immunol 168:2544–2553

    CAS  PubMed  Google Scholar 

  117. Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, Podar K, Hideshima T, Chauhan D, Raje N, Schlossman R, Richardson P, Munshi NC, Anderson KC (2006) Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res 66:6675–6682

    CAS  PubMed  Google Scholar 

  118. Teicher BA, Herman TS, Holden SA, Wang YY, Pfeffer MR, Crawford JW, Frei E 3rd (1990) Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247:1457–1461

    CAS  PubMed  Google Scholar 

  119. Tohda S, Nara N (2001) Expression of Notch1 and Jagged1 proteins in acute myeloid leukemia cells. Leuk Lymphoma 42:467–472

    CAS  PubMed  Google Scholar 

  120. Tu Y, Xu FH, Liu J, Vescio R, Berenson J, Fady C, Lichtenstein A (1996) Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. Blood 88:1805–1812

    CAS  PubMed  Google Scholar 

  121. Urashima M, Ogata A, Chauhan D, Hatziyanni M, Vidriales MB, Dedera DA, Schlossman RL, Anderson KC (1996) Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood 87:1928–1938

    CAS  PubMed  Google Scholar 

  122. Valnet-Rabier MB, Challier B, Thiebault S, Angonin R, Margueritte G, Mougin C, Kantelip B, Deconinck E, Cahn JY, Fest T (2005) c-Flip protein expression in Burkitt’s lymphomas is associated with a poor clinical outcome. Br J Haematol 128:767–773

    CAS  PubMed  Google Scholar 

  123. Veiga JP, Costa LF, Sallan SE, Nadler LM, Cardoso AA (2006) Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival. Exp Hematol 34:610–621

    CAS  PubMed  Google Scholar 

  124. Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–271

    CAS  PubMed  Google Scholar 

  125. Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, Byfield S, Felici A, Flanders KC, Walz TM, Roberts AB, Aplan PD, Balis FM, Letterio JJ (2004) Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 351:552–559

    CAS  PubMed  Google Scholar 

  126. Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M, Sun SC (2001) Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. Embo J 20:6805–6815

    CAS  PubMed  Google Scholar 

  127. Zhang Z, Vuori K, Reed JC, Ruoslahti E (1995) The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci USA 92:6161–6165

    CAS  PubMed  Google Scholar 

  128. Zhou J, Mauerer K, Farina L, Gribben JG (2005) The role of the tumor microenvironment in hematological malignancies and implication for therapy. Front Biosci 10:1581–1596

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematopathology and Laboratory Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL, 33612, USA

    Luis A. Crespo, Xinwei Zhang & Jianguo Tao

Authors
  1. Luis A. Crespo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianguo Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianguo Tao .

Editor information

Editors and Affiliations

  1. Moores UCSD Cancer Center, 3855 Health Sciences Drive 0820, La Jolla, 92093-0820, California, USA

    Boris R. Minev

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Crespo, L.A., Zhang, X., Tao, J. (2011). Targeting the TumorMicroenvironment for Enhancing Chemotherapy in HematologicMalignancies. In: Minev, B. (eds) Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures. Cancer Growth and Progression, vol 13. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9704-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-90-481-9704-0_11

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-90-481-9703-3

  • Online ISBN: 978-90-481-9704-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation