Bioengineering approaches to study multidrug resistance in tumor cells.

The ability of cancer cells to become resistant to chemotherapeutic agents is a major challenge for the treatment of malignant tumors. Several strategies have emerged to attempt to inhibit chemoresistance, but the fact remains that resistance is a problem for every effective anticancer drug. The first part of this review will focus on the mechanisms of chemoresistance. It is important to understand the environmental cues, transport limitations and the cellular signaling pathways associated with chemoresistance before we can hope to effectively combat it. The second part of this review focuses on the work that needs to be done moving forward. Specifically, this section focuses on the necessity of translational research and interdisciplinary directives. It is critical that the expertise of oncologists, biologists, and engineers be brought together to attempt to tackle the problem. This discussion is from an engineering perspective, as the dialogue between engineers and other cancer researchers is the most challenging due to non-overlapping background knowledge. Chemoresistance is a complex and devastating process, meaning that we urgently need sophisticated methods to study the process of how cells become resistant.

[1]  S. Fuqua,et al.  Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. , 2009, Cancer research.

[2]  V. Valero,et al.  Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  Ronald A. DePinho,et al.  Model organisms: The mighty mouse: genetically engineered mouse models in cancer drug development , 2006, Nature Reviews Drug Discovery.

[4]  I. Vergote,et al.  Randomized phase III study of canfosfamide (C, TLK286) plus pegylated liposomal doxorubicin (PLD) versus PLD as second-line therapy in platinum (P) refractory or resistant ovarian cancer (OC). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Martin G Pomper,et al.  Can small animal imaging accelerate drug development? , 2002, Journal of cellular biochemistry. Supplement.

[6]  T. Kunkel,et al.  The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts. , 1998, Cancer research.

[7]  D. Tarin,et al.  Significance of CD44 gene products for cancer diagnosis and disease evaluation , 1992, The Lancet.

[8]  E. Winer,et al.  A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. , 2010 .

[9]  R. Kerbel,et al.  Adhesion-dependent multicellular drug resistance. , 1999, Anti-cancer drug design.

[10]  R. Kerbel,et al.  Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells. , 1996, Journal of the National Cancer Institute.

[11]  J. Doroshow,et al.  Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. , 2001, Blood.

[12]  Marcus Textor,et al.  Engineered 3D environments to elucidate the effect of environmental parameters on drug response in cancer. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[13]  Emil Frei,et al.  Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate , 1961 .

[14]  G. Melillo,et al.  Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy , 2006, Molecular Cancer Research.

[15]  P. Carmeliet,et al.  Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. , 2010, Genes & cancer.

[16]  G. Denis Imatinib Mesylate (Gleevec®) and the Emergence of Chemotherapeuticss Drug-Resistant Mutations , 2008 .

[17]  G. Semenza Targeting HIF-1 for cancer therapy , 2003, Nature Reviews Cancer.

[18]  J. Damiano,et al.  Integrins as novel drug targets for overcoming innate drug resistance. , 2002, Current cancer drug targets.

[19]  Max S Wicha,et al.  Cancer stem cells: an old idea--a paradigm shift. , 2006, Cancer research.

[20]  S. Fulda,et al.  Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance , 2007, Oncogene.

[21]  M. Poupon,et al.  Distinctive alterations of invasiveness, drug resistance and cell–cell organization in 3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant variant , 2004, Clinical & Experimental Metastasis.

[22]  L. Panasci,et al.  DNA-Dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. , 1998, Blood.

[23]  M. Mimeault,et al.  Recent Advances on the Molecular Mechanisms Involved in the Drug Resistance of Cancer Cells and Novel Targeting Therapies , 2008, Clinical pharmacology and therapeutics.

[24]  J. Surrallés,et al.  The Fanconi Anemia/BRCA Pathway: FANCD2 at the Crossroad between Repair and Checkpoint Responses to DNA Damage , 2006 .

[25]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[26]  Christopher Haslett,et al.  Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo , 1999, Nature Medicine.

[27]  R. Sutherland,et al.  Cell contact as a possible contribution to radiation resistance of some tumours. , 1972, The British journal of radiology.

[28]  Celeste M Nelson,et al.  Cell‐cell signaling by direct contact increases cell proliferation via a PI3K‐dependent signal , 2002, FEBS letters.

[29]  I. Pastan,et al.  Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Karran Mechanisms of tolerance to DNA damaging therapeutic drugs. , 2001, Carcinogenesis.

[31]  P B Laub,et al.  Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines. , 1997, Cancer research.

[32]  P. Ratcliffe,et al.  Activation of the HIF pathway in cancer. , 2001, Current opinion in genetics & development.

[33]  Michael Dean,et al.  Tumour stem cells and drug resistance , 2005, Nature Reviews Cancer.

[34]  R. Kerbel,et al.  Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro. , 2004, Molecular cancer therapeutics.

[35]  B. Teicher,et al.  Acquired multicellular-mediated resistance to alkylating agents in cancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[36]  G. Tortora,et al.  In vitro expansion of human breast cancer epithelial and mesenchymal stromal cells: optimization of a coculture model for personalized therapy approaches , 2007, Molecular Cancer Therapeutics.

[37]  N. Altorki,et al.  TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer , 2010, Proceedings of the National Academy of Sciences.

[38]  Z. Wang,et al.  β2-integrins mediate a novel form of chemoresistance in cycloheximide-induced U937 apoptosis , 2004, Cellular and Molecular Life Sciences CMLS.

[39]  Yuan Zhang,et al.  Coculture of bladder urothelial and smooth muscle cells on small intestinal submucosa: potential applications for tissue engineering technology. , 2000, The Journal of urology.

[40]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[41]  S. Sahoo,et al.  3-D tumor model for in vitro evaluation of anticancer drugs. , 2008, Molecular pharmaceutics.

[42]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[43]  S. Kaufmann,et al.  PARP inhibition: PARP1 and beyond , 2010, Nature Reviews Cancer.

[44]  H. Beug,et al.  Molecular requirements for epithelial-mesenchymal transition during tumor progression. , 2005, Current opinion in cell biology.

[45]  A. Beitz,et al.  Secretion of MCP-1 and other paracrine factors in a novel tumor-bone coculture model , 2009, BMC Cancer.

[46]  M. Dewhirst,et al.  Concepts of oxygen transport at the microcirculatory level. , 1998, Seminars in radiation oncology.

[47]  D. Altieri Survivin, versatile modulation of cell division and apoptosis in cancer , 2003, Oncogene.

[48]  L. Griffith,et al.  Capturing complex 3D tissue physiology in vitro , 2006, Nature Reviews Molecular Cell Biology.

[49]  R L Juliano,et al.  A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. , 1976, Biochimica et biophysica acta.

[50]  C. S. Chen,et al.  Geometric control of cell life and death. , 1997, Science.

[51]  Guang-Biao Zhou,et al.  Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[52]  P. Zinzani,et al.  Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma , 2007, Leukemia & lymphoma.

[53]  J. Brown,et al.  Exploiting tumour hypoxia in cancer treatment , 2004, Nature Reviews Cancer.

[54]  H. Takeuchi,et al.  New-generation efflux pump inhibitors , 2008, Expert review of clinical pharmacology.

[55]  S. Cole,et al.  Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. , 2006, Physiological reviews.

[56]  H. Chakrapani,et al.  Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound. , 2008, Bioorganic & medicinal chemistry.

[57]  C. Sotiriou,et al.  Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? , 2007, Nature Reviews Cancer.

[58]  D. Hussein,et al.  Chronic hypoxia promotes hypoxia-inducible factor-1α–dependent resistance to etoposide and vincristine in neuroblastoma cells , 2006, Molecular Cancer Therapeutics.

[59]  S. Gerson MGMT: its role in cancer aetiology and cancer therapeutics , 2004, Nature Reviews Cancer.

[60]  C. L. La Porta,et al.  Cancer stem cells and therapeutic perspectives. , 2006, Current medicinal chemistry.

[61]  J. Ioannidis,et al.  The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma , 2003, Cancer.

[62]  Y. Hishikawa,et al.  Overexpression of metallothionein correlates with chemoresistance to cisplatin and prognosis in esophageal cancer. , 1997, Oncology.

[63]  Richard P. Hill,et al.  The hypoxic tumour microenvironment and metastatic progression , 2004, Clinical & Experimental Metastasis.

[64]  D. Durocher,et al.  DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? , 2001, Current opinion in cell biology.

[65]  T. Sakaeda,et al.  An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. , 2006, Current pharmaceutical design.

[66]  G. Semenza,et al.  Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. , 2003, Cancer research.

[67]  A. Rzhetsky,et al.  The human ATP-binding cassette (ABC) transporter superfamily. , 2001, Genome research.

[68]  R. Arceci,et al.  Phase I study of valspodar (PSC‐833) with mitoxantrone and etoposide in refractory and relapsed pediatric acute leukemia: A report from the Children's Oncology Group , 2010, Pediatric blood & cancer.

[69]  L. Matrisian,et al.  Matrix metalloproteinases in tumor-host cell communication. , 2002, Differentiation; research in biological diversity.

[70]  R. Ozols,et al.  Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. , 1991, Cancer Research.

[71]  A. Townsend,et al.  Dynamics of glutathione conjugation and conjugate efflux in detoxification of the carcinogen, 4-nitroquinoline 1-oxide: contributions of glutathione, glutathione S-transferase, and MRP1. , 2005, Biochemistry.

[72]  J. Hardwick,et al.  Upgrading the BCL-2 Network , 2006, Nature Cell Biology.

[73]  R J Carroll,et al.  Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. , 2000, Controlled clinical trials.

[74]  A. Strasser,et al.  The BCL-2 protein family: opposing activities that mediate cell death , 2008, Nature Reviews Molecular Cell Biology.

[75]  G. Giaccone,et al.  A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183 , 2007, Clinical Cancer Research.

[76]  J. Tschopp,et al.  The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex* , 2002, The Journal of Biological Chemistry.

[77]  Michael L Maitland,et al.  Terminal Ballistics of Kinase Inhibitors: There Are No Magic Bullets , 2006, Annals of Internal Medicine.

[78]  M. Mimeault,et al.  Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[79]  W. V. van Weerden,et al.  Use of nude mouse xenograft models in prostate cancer research , 2000, The Prostate.

[80]  B. Cheson,et al.  Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. , 2009, Blood.

[81]  J. Rosen,et al.  Stem cells in the etiology and treatment of cancer. , 2006, Current opinion in genetics & development.

[82]  O. Olopade,et al.  FANCF methylation contributes to chemoselectivity in ovarian cancer. , 2003, Cancer Cell.

[83]  Qingcheng Mao,et al.  Role of the breast cancer resistance protein (ABCG2) in drug transport , 2005, The AAPS Journal.

[84]  K. Shakesheff,et al.  Liver tissue engineering: a role for co-culture systems in modifying hepatocyte function and viability. , 2001, Tissue engineering.

[85]  D. McDonald,et al.  Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. , 2003, The American journal of pathology.

[86]  Jean-Pierre Gillet,et al.  Mechanisms of multidrug resistance in cancer. , 2010, Methods in molecular biology.

[87]  K. Black,et al.  Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma , 2006, Molecular Cancer.

[88]  J. Erler,et al.  Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1 , 2006, Molecular Pharmacology.

[89]  S. Kaye,et al.  Drug resistance reversal--are we getting closer? , 2003, European journal of cancer.

[90]  R. Bociek,et al.  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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  D. Hamer,et al.  Overexpression of metallothionein confers resistance to anticancer drugs. , 1988, Science.

[92]  M. Mimeault,et al.  Concise Review: Recent Advances on the Significance of Stem Cells in Tissue Regeneration and Cancer Therapies , 2006, Stem cells.

[93]  C. S. Chen,et al.  Control of cyclin D1, p27(Kip1), and cell cycle progression in human capillary endothelial cells by cell shape and cytoskeletal tension. , 1998, Molecular biology of the cell.

[94]  M. Textor,et al.  single cells{ , 2007 .

[95]  Michael C. Ostrowski,et al.  Genomic alterations in tumor stroma. , 2009, Cancer research.

[96]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.

[97]  A. Pandey,et al.  Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. , 2008, Cancer research.

[98]  F. Alt,et al.  Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation , 1995, Cell.

[99]  Frank Pajonk,et al.  The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. , 2006, Journal of the National Cancer Institute.

[100]  D. Townsend,et al.  The role of glutathione-S-transferase in anti-cancer drug resistance , 2003, Oncogene.

[101]  Monica Hoyos Flight Drug screening: Shedding light on tumour–stroma interactions , 2010, Nature Reviews Drug Discovery.

[102]  Ian F Tannock,et al.  The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors , 2009, BMC Cancer.

[103]  B. Toole,et al.  Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[104]  U Kneser,et al.  Modulation of in vitro angiogenesis in a three-dimensional spheroidal coculture model for bone tissue engineering. , 2004, Tissue engineering.

[105]  Z. Estrov,et al.  Eradication of Leukemia Stem Cells as a New Goal of Therapy in Leukemia , 2006, Clinical Cancer Research.

[106]  Jiaquan Xu,et al.  Deaths: final data for 2006. , 2009, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[107]  D. Fisher,et al.  A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/Akt in colon carcinoma cells. , 2001, Cancer research.

[108]  D. Gandara,et al.  Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. , 2002, Seminars in oncology.

[109]  R. Herbst,et al.  Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1{alpha}. , 2010 .

[110]  W. Dalton The tumor microenvironment as a determinant of drug response and resistance. , 1999, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[111]  A. Tutt,et al.  Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  Crispin J. Miller,et al.  Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance , 2004, Molecular and Cellular Biology.

[113]  J. Xu,et al.  Extracellular matrix alters PDGF regulation of fibroblast integrins , 1996, The Journal of cell biology.

[114]  J. Massagué,et al.  Beyond tumorigenesis: cancer stem cells in metastasis , 2007, Cell Research.

[115]  James M. Roberts,et al.  Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein , 1996, The Journal of cell biology.

[116]  Yoshimasa Tanaka,et al.  Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[117]  A. Zhu,et al.  Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors , 2007, Cancer Chemotherapy and Pharmacology.

[118]  C. Craddock,et al.  Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. , 2000, Blood.

[119]  K. Anderson,et al.  Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anti-cancer drug activity , 2010, Nature Medicine.