From Chemoresistance to Hope

The three treatments that cancer patients most frequently receive are surgery, radiation, and chemotherapy. Even while surgery is sometimes successful, many cancers respond better to a combination of radiotherapy and chemotherapy. Modern chemotherapeutic agents can effectively treat the initial tumour and any leftovers that remain after surgery or radiation. However, chemotherapy can diverse tumours made up of both healthy and cancerous cells, and diversity within tumours lowers the effectiveness of chemotherapy, resulting in treatment failure and disease progression.

It has been established that tumours can develop because of the uncontrollable changes of even a single normal cell, most likely due to the build-up of many genetic abnormalities. According to mounting data, the cancer stem cell (CSC) population is a subpopulation of cancer cells that may self-renew and become diverse lineages of cancer cells in response to chemotherapeutic treatments. These CSCs are believed to be the reason cancer becomes chemo-resistant and relapses. Several studies have indicated that CSCs are very similar to stem cells, and it has been found that CSCs accumulate changes or mutations in important pathways that are essential in the maintenance of normal stem cells.

90% of deaths from breast cancer and other solid tumours are caused by cancer metastasis. Breast cancer metastasis is mainly due to Circulating tumour cells (CTCs) that shed from the main tumour, enter the circulation, and spread to other organs for tumour regrowth, a process known as “metastatic seeding.” When these cells develop into multicellular CTC clusters which then acquire changes in these normal pathways and change to CSC characteristics, the risk of metastasis increases 20–100-fold. 

A demonstration of this theory of CSCs using a simple blood transplant with “purified” bone marrow in combination with chemotherapy in breast cancer patients:

In the early 1980’s and 90’s, many breast cancer patients were given high-dose chemotherapy to eradicate the disease. These patients were “rescued” with an infusion of their own bone marrow cells, which were taken prior to chemotherapy, as the chemotherapy also killed the blood and immune stem cells. However, high-dose chemotherapy was not offered in metastatic disease along with the bone marrow transplant. The issue was that most these patients’ bone marrow samples also included cancer stem cells because cancer stem cells had disseminated throughout the body.

Researchers at Stanford in 2011 chose to purify the bone marrow stem cells by removing any roaming cancer cells and regular blood by using antibodies that recognised newly discovered markers on the surface of the blood stem cells. They used this in 22 women with metastatic breast cancer who enrolled in the experiment from December 1996 to February 1998 and were then treated with this pure population of stem cells. They also used unpurified bone marrow as the usual treatment in another 74 women with metastatic breast cancer. The years went by as they waited. In the experimental group, 22% of women survived disease-free after 5-10 years; in the control group, only 9% survived after 2 years.

Currently, the development of CSC-targeting drugs, vaccinations, antibodies, and CAR-T cells all aim to block these processes in CSCs. The results of numerous CSC clinical trials in metastatic breast cancer have been encouraging. Although these methods for targeting CSCs are still hindered by a few challenges, which should soon be overcome; it will open new possibilities for the treatment of cancer patients.

Breast cancer stem cells can alter their internal plasticity programmes and exterior facial features in several dynamic ways, just like circulating tumour stem cells, to adapt to difficult situations, including therapies and metastasis. In order for us to create the best defences against their evasion and spread, targeting these dangerous cancer cells with novel medicines, and ultimately saving the lives of patients; we must be aware of every trick and strategy that circulating tumour stem cells use.