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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Acute and chronic in vivo therapeutic resistance

Beverly A Teicher1

  • 1Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA. beverly.teicher@genzyme.com

Biochemical Pharmacology
|May 12, 2009
PubMed

Insights

Host normal tissues and tumor microenvironment factors significantly drive therapeutic resistance in cancer. Understanding these complex interactions is crucial for developing effective anticancer treatments.

Area of Science:

  • Oncology
  • Cancer Biology
  • Tumor Microenvironment

Background:

  • Host normal tissue response and engagement are key factors in cancer therapeutic resistance.
  • Solid tumors exhibit physical stresses like hypoxia and acidosis, promoting aggressive phenotypes.
  • Soluble factors from malignant and normal cells shape the tumor microenvironment, supporting tumor growth and survival.

Purpose of the Study:

  • To elucidate the multifaceted roles of host tissues and the tumor microenvironment in driving therapeutic resistance.
  • To highlight the impact of physical stresses and soluble factors on malignant disease progression.
  • To underscore the contribution of various host cells to tumor growth and immune evasion.

Main Methods:

  • Review and synthesis of existing literature on tumor-host interactions and therapeutic resistance.
  • Analysis of the molecular mechanisms underlying physical stress responses in tumors (e.g., HIF, GLUT-1).
  • Examination of the signaling pathways involving key factors like transforming growth factor-beta (TGF-β).

Main Results:

  • Physical tumor stresses (hypoxia, acidosis) activate pathways leading to metabolic alterations and pro-angiogenic factor secretion.
  • Transforming growth factor-beta (TGF-β) promotes angiogenesis, extracellular matrix deposition, immune tolerance, and epithelial-mesenchymal transition.
  • Various host cells, including endothelial cells, mesenchymal stem cells, and immune cells (Tregs, macrophages), actively support tumor growth and immune evasion.
  • Complex in vivo interactions, not easily replicated in vitro, contribute significantly to therapeutic resistance.

Conclusions:

  • Therapeutic resistance in cancer is significantly influenced by the complex interplay between tumor cells, host normal tissues, and the tumor microenvironment.
  • Non-genetically based resistance mechanisms arising from these interactions are clinically relevant.
  • Further research into these in vivo dynamics is essential for overcoming treatment challenges.

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