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Cancer stem cells: Prime targets in the war against cancer

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While there is increasing scientific evidence that points to stem cells as the origin of tumours, the mechanism by which these cells go rogue is not well understood.

Annapoorni Rangarajan, an assistant professor at the Department of Molecular Reproduction, Development and Genetics at the Indian Institute of Science, Bangalore, has been studying this problem for seven years now. In a paper published a couple of months ago in Oncogene, a leading cancer journal under the umbrella of the Nature group, Rangarajan, along with her colleagues at IISc, Kidwai Memorial Hospital, Bangalore and the Indian Institute of Science Education and Research, Pune, has shown, perhaps for the first time, that ‘immortalised’ tumour cells can be generated from stem-like cells by adding genetic elements. While previous experiments have turned non-stem cells into cancerous cells using similar methods, Rangarajan and her colleague AN Paranjape have been able to show that stem-like cells undergo tumorigenic transformation more easily.

“An easy way to tell stem-like cells from differentiated cells is by their adherence. When cells are cultured, stem-like cells tend not to attach to the surface of the dish and can form colonies floating in a liquid medium. Differentiated cells have to stick to the bottom of the dish to grow,” says Rangarajan. To normal stem-like cells taken from human breast tissue, Rangarajan added Simian Virus 40 Early Region (SV40ER) and human telomerase (hTERT), both of which have been used to induce tumorigenic transformation before. SV40ER generates antigens that act against tumour suppressors with the cell, and telomerase, the enzyme necessary to lengthen telomeres—DNA sequences present at the end of chromosomes that grow shorter with each cell division—is a catalyst. What she did not add was the oncogenic protein ‘Ras’, considered a necessary part of the cocktail that induces tumorigenic transformation.

The resultant cells, the paper says, “retained stem-like properties, contained a sub-population resembling breast CSCs and generated invasive breast adenocarcinomas”. “Furthermore, gene expression profiling revealed a close resemblance with naturally arising tumours. Thus, our study provides a novel breast cancer model system to begin to understand the molecular mechanisms involved in the transformation of primitive breast cells with stem-like properties,” it adds.

The experiment, by showing that stem cells require fewer genetic alterations to turn cancerous, suggests that cancer stem cells might be more closely linked to stem cells than was previously thought. Like stem cells, CSCs have many ways of dividing. The first way is symmetric, leading to the cell cloning itself. In asymmetric division, a CSC will divide into one CSC and one differentiated cell, thus forming a colony of cells that are not cancerous. These cells, which form the bulk of the tumour (up to 90 per cent), can only divide a few times before they die. CSCs, unfortunately, can multiply indefinitely and are known to be inherently resistant to cancer drugs. Chemotherapy, while it kills differentiated cells in a tumour, doesn’t seem to touch CSCs, possibly explaining the recurrence of cancer in treated patients.

Rangarajan says her lab, with access to a mice facility as well as pathological samples of tissue from human patients, is now poised to study the self-renewal mechanism of tumour-propagating cells in breast cancer. The incidence of breast cancer is on the rise in Indian cities, especially among younger women. “The idea is to study patient biopsies over a period of time and then use that knowledge to predict the fate of the treatment in say, 15 days of labwork. Imagine what that could do to help the doctor reach a decision on the course of treatment,” she says.

Labs across the world are working towards developing a targeted therapy that can kill CSCs, but the solution could be tricky. “Stem cells and cancer stem cells are two sides of the same coin. In fact, cancer hijacks the mechanism of normal stem cells for its selfish purposes,” Rangarajan says. Which means that while stem cell therapy can come with the risk of cancer in the long run, cancer therapy that destroys CSCs can also end up targeting regular stem cells.

Furthermore, recent research published in the journal Cell suggests that cancer cells may not have fixed hierarchical roles—as CSCs or otherwise—but that they can switch between the two. This in-vitro model, which proposes that non-stem cells in a tumour can at any time convert to being cancer stem cells, hasn’t been tested in vivo. As Rangarajan says, “The more we learn about cancer, the less we understand it.”