Writing in Cancer Treatment Reviews, researchers discuss the mechanisms by which cancer stem cells (CSCs) become resistant to therapy, and make 5 recommendations for advancing research in this area.1

CSCs are undifferentiated, tumorigenic, and more resistant to chemotherapy and radiotherapy than differentiated cancer cells. Following therapy, CSCs that survive often acquire a more aggressive phenotype that is also more resistant to treatment, leading to relapse and metastasis. Understanding how they do this is an important goal, said the authors.

“Understanding the mechanisms that underlie CSC maintenance to combat cancer is essential,” said study co-author Matilde E. Lleonart, PhD, of the Vall d’Hebron Research Institute in Barcelona, Spain, in an email to Cancer Therapy Advisor. “Determining the mechanisms that govern radio/chemoresistance in CSCs may illuminate the origins of this complex process and improve the treatments of cancer.”

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The researchers reviewed several proposals that attempted to explain CSCs’ resistance to conventional therapy. These include activation and overexpression of drug transporter proteins, stem cell pathway activation, accelerated cellular metabolism, altered expression of detoxifying enzymes, impaired autophagy, more efficient DNA repair, resistance to apoptotic and senescence pathways, and interactions between CSCs and their microenvironments.

The authors discussed the understood mechanisms by which each of these proposals operate, and reviewed the efficacy of experimental treatments that target them. Targeting cellular transporters and membrane receptors was successful in some instances; combination therapies that target CSCs, for example, were effective in basal cell carcinoma, but less so for other cancers. Small molecules that act against components of the extracellular matrix may be able to prevent CSCs from manipulating the microenvironment.

“Our article reinforces the impact of CSC therapy, but also raises some important issues to consider when a CSC therapy is applied,” said Dr Lleonart. “First we need to classify those tumors predictable for a successful CSC therapy. By doing that, it would be possible to predict those patients where a CSC-therapy in combination with standard therapy will be effective. Even for specific tumor types, we need to do such patient identification/stratification to assure therapeutic success.” 

The researchers offer 5 conclusions for advancing CSC research:

  1. It’s important to define specific CSC markers to “precisely annihilate” CSCs.
  2. Researchers need to determine the mechanisms governing CSC resistance to conventional therapy.
  3. Conventional anti-cancer therapies may transform the CSC microenvironment, disturbing anticancer homeostatic mechanisms.
  4. Combination therapies including drugs that target CSCs specifically may be the best approach, particularly for highly aggressive tumors with poor prognosis.
  5. Animal models are needed to optimize therapeutic treatments for use in concomitant administration.

Dr Lleonart’s research group is focused on developing CSC drug screens directed against CSCs themselves, as well as identifying specific CSC proteins from particularly aggressive tumors.

“Research should focus on the establishment of accurate preclinical animal models to discover real drug combinations in a context where patient-derived xenograft models could be monitored at any stage, to demonstrate the effects of drugs at genetic and protein levels in CSC and non-CSC populations,” she said. 


  1. Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT, Lleonart ME. The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev. 2016 Jul 9;49:25-36. doi: 10.1016/j.ctrv.2016.07.001