Somatic Cells Become Cancer’s “Starter Dough”

In vitro transformation induces reprogramming of differentiated fibroblasts and confers cancer-stem-cell (CSC) properties. Acquisition of self-renewal and differentiation ability allows reprogrammed somatic cells to initiate and maintain tumors. During tumor growth, SSEA-1+ CSCs differentiate into phenotypically diverse, non-tumorigenic cancer cells, thereby generating heterogeneous and hierarchically-organized tumors.

In vitro transformation induces reprogramming of differentiated fibroblasts and confers cancer-stem-cell (CSC) properties. Acquisition of self-renewal and differentiation ability allows reprogrammed somatic cells to initiate and maintain tumors. During tumor growth, SSEA-1+ CSCs differentiate into phenotypically diverse, non-tumorigenic cancer cells, thereby generating heterogeneous and hierarchically-organized tumors.

Cancer stem cells (CSCs) is a term that sparks animated differences of opinions among researchers in the oncology community.  Much of the disagreement comes from the difficulty involved in isolating these cells and manipulating them ex vivo. When putative CSCs are isolated from clinical samples, researchers are unable to retrospectively identify the cell type that suffered the first oncogenic hit that led to tumorigenesis. Without this ability to make a clear pre- and post-cancer comparison, researchers are unable to characterize with confidence the origin and cellular properties of human CSCs.

In a recent paper in Nature Cell Biology, Paola Scaffidi, Ph.D.,  and Tom Misteli, Ph.D., working in CCR’s Laboratory of Receptor Biology and Gene Expression reported findings that may bring some clarity to this topic. 

The scientists compared two non-tumorigenic immortalized human fibroblast cell lines with their corresponding tumorigenic cell lines generated through in vitrotransformation in terms of the CSC and embryonic stem cell (ESC) markers they bore. Several of the well known ones displayed similar expression levels in both the immortalized and the transformed fibroblast lines.  But the team also discovered an important difference.  An ECS early differentiation antigen called SSEA-1 was present in the transformed fibroblast lines and absent in the immortalized control cell line.

Using a competitive tumor development model to further characterize the SSEA-1+ subpopulation, Scaffidi and Misteli showed that this subgroup of cells which arises during in vitro transformation of fibroblasts possesses all functional properties of CSCs and drives tumor initiation and maintenance.  SSEA1+ cells have self-renewal potential, are multipotent, and generate hierarchically organized tumors by differentiating into non-fibroblastic, non-tumorigenic cancer cells. In fact, their cell sorting experiments showed that a single SSEA1+ transformed fibroblast cell can potentially initiate a heterogeneous collection of tumors.

Scaffidi and Misteli showed that CSCs are molecularly distinct from SSEA-1– cells in the population of transformed fibroblasts, and they are also distinct from their differentiated progeny within tumors. It thus appears that somatic cells possess enough plasticity to reprogram and acquire CSC-like properties upon oncogenic insults in vitro, and they may act as “starter dough” for cancer.

The team hopes that the ability to generate cells with CSC properties in vitro will be a useful tool for the molecular characterization of stem-like behavior in cancer. While rare and heterogeneous CSC populations isolated from clinical samples cannot be easily characterized and manipulated, in vitro-generated CSCs can be directly compared to their noncancerous counterpart.  Hopefully, what scientists learn about self-renewal capabilities in this experimental system of transformed fibroblastic cells will uncover mechanisms of tumorigenicity of importance when applied to analysis of clinical samples.

Summary Posted: 08/2011

Reference

http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb2308.html Reviewed by Donna Kerrigan PubMed Link