From autonomy to community; new perspectives on tumorigenicity and therapy resistance

- Intratumor heterogeneity is the foundation of resistance to therapy.
- The CSC theory was launched as an explanation to intratumor heterogeneity.
- Differentiation stage and phenotype of CSC can change during disease progression.
- Patient derived xenografts allow studies of cancer cell populations in their niche.

Subclones of cancer cells evading treatment represent the major challenge in oncology. Despite recent advances, tumors not responding to treatments are still a severe risk to cancer patients, and oncologists have, as of now, little effective therapy to offer patients with systemic cancer disease. The widely discussed cancer stem cell (CSC) paradigm was originally launched as an explanation to the existence of small cell populations resistant to therapy within the heterogeneous tumor, but has so far unfortunately, offered little concrete improvement in cancer treatment regimes. The launch of the CSC hypothesis did, however, highlight the significance of therapy targeting specific tumor-driving processes, and even more importantly, an increased awareness of a phenomenon well known to stem cell researchers; non-genetic phenotypic heterogeneity of cells with common origin. Here, the scientific background of the CSC theory is revisited and the evidence for CSCs is discussed, along with the importance of considering CSC's dependency of their habitat for survival and growth. Furthermore, recent advances in cancer cell heterogeneity and new possibilities for studying therapy responses in cell clones within the natural tumor environment using patient derived xenograft (PDX) models, are reviewed.