Melanoma 'stem cells': ABCB5 molecule holds key to growth, metastasis

Key Points

Boston - Melanoma cells expressing the ABCB5 molecule on their surface are key players in the growth and metastasis of that deadly tumor, according to a paper published in Nature on Jan. 17.

The molecule offers an exciting new target for intervention.

The term "cancer stem cell" is used, because "Hierarchically, the cell gives rise to more copies of itself, as well as to other differentiating non-tumorigenic cells within the cancer," Dr. Frank tells Dermatology Times.

The origin of such cells remains unclear; it may be that a true physiological stem cell has become cancerous, or it may be that "a somatic cell accrues mutations that essentially make it act this way," he says.

Marker of progression

Dr. Frank found that primary or metastatic melanoma expressed significantly more ABCB5 on the cell surface than benign melanocytic nevi; thick primary melanomas more than thin primary melanomas; and melanomas metastatic to lymph nodes more than primary lesions, thus demonstrating that it is a marker of neoplastic progression.

When implanted in the mouse model, ABCB5⁺ melanoma cells showed a robust capacity to produce both ABCB5⁺ and ABCB^- cells.

ABCB^- cells did not differentiate; they produced only ABCB^- cells and did so at a lower rate than cells that expressed the molecule.

There also was a dose response; animals receiving greater numbers of ABCB5⁺ cells were more likely to develop tumors.

Administration of an anti-ABCB5 monoclonal antibody significantly inhibited tumor growth and formation.

The ABC family of molecules are membrane transporters that shuttle compounds from inside the cell to the membrane and have been associated with the phenotype of physiological stem cells.

"They are thought to provide a primitive mechanism of protection against xenobiotics. So, there appears to be a similarity in the phenotype of a cancer stem cell having this particular pump, with the physiological stem cell.

"But the direct connection has not been causally established," Dr. Frank says.

Dr. Frank had shown in earlier work that ABCB5 contributes to resistance to chemotherapy by exporting drugs, such as doxorubicin, from the inside of the cell to the outside, thereby, reducing intracellular drug accumulation.

In vitro, blockade of the molecule increased intracellular accumulation of doxorubicin and induced cell death.

The monoclonal approach would target the most aggressive components of the tumor, but would not have any effect on cells that do not express ABCB5, which constitute the bulk of the tumor.

So, it is likely that an ABCB5 monoclonal antibody will be used in combination with established therapies, perhaps with a synergistic effect.