Changing Cancer Cells Back to Normal Cells

A new study using a novel experimental approach provides unique insights into how scientists can change human metastatic melanoma cells back to normal-like skin cells--by exposing the tumor cells to the embryonic microenvironment of human embryonic stem cells in the zebra fish and the chick embryo.

In earlier studies, scientist Dr. Mary J.C. Hendrix and colleagues from Northwestern University (Evanston, IL, USA) discovered that aggressive melanoma cells (but not normal skin cells nor less aggressive melanoma cells) contain specific proteins similar to those found in embryonic stem cells. This groundbreaking study led to the first molecular classification of malignant melanoma, and may help to clarify how, by becoming more like unspecialized stem cells, aggressive melanoma cells gained enhanced abilities to migrate, invade, and metastasize while moving virtually unnoticed by the immune system.

Dr. Hendrix presented her findings at the American Association of Anatomists' plenary lecture and symposium, at the Experimental Biology 2007 meeting in Washington, DC, USA, on April 29, 2007.

Embryonic stem cells are pluripotent, meaning they are able to differentiate into any of the more than 200 cell types in the adult body. Which type of cell they become depends on the signals they receive from their microenvironment. Likewise, during cancer progression, malignant cells receive and release signals from their own microenvironment, cues that promote tumor growth and metastasis.

To better determine what signals the melanoma cells are sending and receiving, Dr. Hendrix and her colleagues utilized the microenvironment of the zebrafish to assess whether the tumor cells could communicate with the zebrafish stem cells and affect their early development. The zebrafish is a prolific reproduction, rapid development, and transparent embryo that develops outside the body, and develops organs and tissues comparable to those in humans, such as heart, kidney, pancreas, bones, and cartilage.

Using the zebrafish model, and the extraordinary recent technologic developments made in microscopy and molecular biology, the team was able to show that the aggressive melanoma cells secrete Nodal, a vital component underling the two-way communication between tumor cells and the embryonic microenvironment. Nodal is an embryonic factor (also called a morphogen) responsible for maintaining the pluripotency of human embryonic stem cells: their ability to develop or "morph” into one of a host of body cells. When aggressive melanoma and other tumor cells (recent findings also report Nodal expression in breast cancer and testicular cancer) regain the ability to express a potent embryonic morphogen such as Nodal, the presence of the Nodal and the signals it sends and receives appear to play a major role in tumor cell plasticity and progression.

Most striking, Dr. Hendrix's team also has shown that inhibition of Nodal signaling leads to a reduction in melanoma cell invasiveness and ability to create new tumors. In fact, with inhibition of Nodal, the metastatic melanoma cells are reverted to a more benign skin cell without the ability to form tumors.

Findings from the zebrafish study were additionally confirmed in the human embryonic stem cell model and the chick embryo model--where suppressing Nodal signaling led to the reversal of the melanoma cells to a more normal cell type.

This is a promising area of research, according to Dr. Hendrix. The findings of a new signalizing pathway in melanoma and other tumor cell types, and the ability to inhibit Nodal and thus reverse the melanoma cell back toward a normal skin cell provide a previously unknown target for regulating tumor progression and metastasis.


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