Skip to main content
Article thumbnail
Location of Repository

Systems Biology: A Therapeutic Target for Tumor Therapy

By Albrecht Reichle and Thomas Vogt


Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems’ stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans’ cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/− dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects as adjustable sizes available for targeted biomodulatory therapies

Topics: Original Paper
Publisher: Springer Netherlands
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2007). A et al (2007) Induction of complete remission in metastatic hormone-refractory prostate cancer: a combined anti-inflammatory therapy approach. [abstract].
  2. (2006). Adult stem cell theory of the multistage, multi-mechanism theory of carcinogenesis: role of inflammation on the promotion of initiated cells. In: Dittmar T, Zaenker KS, Schmidt A (eds) Infections and inflammation: impacts on oncogenesis.
  3. Almushatat AS et al (2006) Systemic inflammatory response, prostate-specific antigen and survival in patients with metastatic prostate cancer.
  4. (2003). Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors.
  5. (2006). Antiangiogenic therapy in metastatic prostate carcinoma complicated by cutaneous lupus erythematodes.
  6. (2005). Antiinflammatory and angiostatic therapy in chemorefractory multisystem Langerhans’ cell histiocytosis of adults.
  7. (2004). Antimetastatic activity of a cyclooxygenase-2 inhibitor.
  8. (2006). C-reactive Protein in patients with metastatic clear cell renal carcinoma: an important biomarker for tumor-associated inflammation.
  9. (2004). Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial.
  10. (2006). Complete remission of relapsing high-grade angiosarcoma with single-agent metronomic trofosfamide.
  11. Crighton F et al (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma.
  12. (2006). Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression.
  13. DebrockG,VanhentenrijkV,SciotRetal(2003)AphaseIItrialwith rosiglitazone in liposarcoma patients.
  14. (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
  15. Elmlinger MW et al (2003) Hypoglycemia associated with the production of insulin-like growth factor (IGF)-II by a hemangiopericytoma. Dtsch Med Wochenschr 128:257–260
  16. et al (2005) Oct-4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis.
  17. (2004). Friends or foes – bipolar effects of the tumour stroma in cancer.
  18. (2007). Gap junction intercellular communication as a ‘Biological Rosetta Stone’ in understanding, in a systems manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy.
  19. (2002). Gap junctions as therapeutic targets. Current Drug Targets 3:465–482
  20. (2006). High-dose celecoxib and metronomic “low-dose” cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin’s lymphoma.
  21. Huang S et al (2007) PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One 2:260e
  22. (2004). Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes.
  23. (1994). Hyltander A et al
  24. (2007). Hypoxia signalling controls metabolic demand.
  25. (1966). Intercellular communication and the control of growth: lack of communication between cancer cells.
  26. (2005). Molecular determinants of crosstalk between nuclear receptors and toll-like receptors.
  27. (2005). New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARgamma agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy. Curr Cancer Drug Targets 5:393–
  28. (2007). Non-steroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon.
  29. (2007). Pharmacodynamic and pharmacokinetic studies of low-dose metronomic cyclophosphamide in mice.
  30. (2004). Pioglitazone and Rofecoxib combined with angiostatically scheduled capecitabine in far-advanced hepatobiliary carcinoma. Medimond S r l,
  31. (2004). Pioglitazone and rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma.
  32. (2008). PPARgamma agonists can be expected to potentiate the efficacy of metronomic chemotherapy through CD36 up-regulation. Med Hypotheses 70:419–23
  33. (2004). Progressive dysregulation of transcription factors NF-kappa B and STAT1 in prostate cancer cells causes proangiogenic production of CXC chemokines.
  34. (1995). Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma.
  35. (2000). Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.
  36. (2004). Regulation of cytokine receptor signaling by nuclear hormone receptors: a new paradigm for receptor interaction.
  37. (2007). Reichle A
  38. Reichle A et al (2004) Antiangiogenic therapy with pioglitazone, rofecoxib, and trofosfamide in a patient with endemic kaposi sarcoma.
  39. (1993). Reversal of rasinduced inhibition of gap junctional intercellular communication, transformation, and tumorigenesis by lovastatin.
  40. Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.
  41. (2005). Suberoylanilide hydroxamic acid enhances gap junctional intercellular communication via acetylation of histone containing connexin43 gene locus.
  42. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
  43. (2007). Targeted combined antiinflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial.
  44. (2003). The role of stem cells and gap junctional intercellular communication in carcinogenesis.
  45. (1987). Thrombosis and cancer.
  46. (1998). Treatment of advanced renal cell cancer with recombinant interferon alpha as a single agent and in combination with medroxyprogesterone acetate. A randomized multicenter trial.
  47. Trosko JE et al (2007) Expression of the embryonic transcription factor Oct4 in canine Systems biology: a therapeutic target for tumor therapy 169neoplasms: a potential marker for stem cell subpopulations in neoplasis.
  48. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
  49. Urbanska K et al (2006) Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt.
  50. (2007). Vascular endothelial growth factor and its relationship to inflammatory mediators.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.