Cancer Stem Cells and Resistance to Drugs

Stem cells are responsible for the generation of all tissues and organs within the body. When these cells become mutated at the gene level (DNA), they become cancerous and are named cancer stem cells [1]. These cancer cells are thought to provide resistance to chemotherapy and relapse in cancer patients.

The mutations can affect embryonic stem cells, leading to teratomas or adult stem cells resulting in tissues specific cancers.

Cancer stem cells are a primary barrier for successful cancer therapy due to their role in the resistance to cancer and in cancer relapse which accounts for approximatively 90% of cancer-related deaths [1].

I. What Is Chemotherapy?

For the treatment of cancer, chemical compounds are used to target the DNA of cancer cells to induce their death.

Due to the high rate of division of cancer cells, chemotherapy can easily attach to the DNA of cancer cells and induce breakages or block their metabolism which results in the activation of the death program within the cancer cells to get rid of them [1].

Unfortunately, chemotherapy can lead to chemotherapy side effects on normal cells that have a high rate of division, such as hair follicle cells, which leads to hair loss.

Therefore, the aim of any chemotherapy is to kill cancer cells with a minimum toxic effect on normal cells.

II. What Are the Types of Chemotherapy?

They are different types of chemotherapy that are grouped into alkylating agents, antimetabolites, plant alkaloids, and antitumor antibiotics [2].

1- What Are Alkylating Agents?

Alkylating agents are the most used chemotherapy drugs. They are compounds that attach to the DNA of cancer cells to cause breakages (damages) which stop the cancer cells from dividing, and therefore, trigger their death.

Among the alkylating agents used for chemotherapy are cisplatin, cyclophosphamide, chlorambucil, busulfan, lomustine, semustine, carmustine, thiotepa, and dacarbazine.

2- What Are Antimetabolites?

Antimetabolites are compounds that are used to “trick” enzymes of cancer cells to consume and use as nutrients for their enzymatic reactions.

They are meant to replace normal nutrients with inefficient ones (antimetabolites) to starve the cancer cells leading to their death.

Examples of antimetabolites that are used in chemotherapy include methotrexate, 6-mercaptopurine; 5-fluorouracil, fludarabine, gemcitabine, pemetrexed, and cytarabine.

3- What Are Plant Alkaloids?

These drugs are chemicals naturally produced by plants and act specifically on the division cycle of cancer cells (cell cycle).

Among the plant alkaloids agents used for chemotherapy are doxorubicin, actinomycin D, and mitomycin.

4- What Are Antitumor Antibiotics?

The DNA of cells, including cancer cells, is packed in the nucleus in a form of structures known as nucleosomes. For the DNA (and therefore genes) to be able to express a messenger RNA for proteins synthesis, nucleosomes must open.

Antitumor antibiotics prevent the opening of the nucleosomes, which prevents gene expression and protein synthesis necessary for the survival of cancer cells.

Examples of antitumor antibiotics that are used in chemotherapy include anthracyclines (e.g., epirubicin, doxorubicin, daunorubicin, mitoxantrone, and idarubicin), actinomycins (e.g., plicamycin and dactinomycin), bleomycin, and mitomycin.

III. How Do Cancer Stem Cells Resist Chemotherapy?

Cancer stem cells (CSCs) are associated with the presence of cancer-related mechanisms that allow them to resist cancer therapies, and therefore, contribute to a tumor being aggressive [1].

1- Dormancy

Cancer stem cells can stop dividing and enter a dormancy state which limits the effect of chemotherapeutic compounds that target highly dividing cells.

2- The ATP-binding cassette family of transporters

Cancer stem cells express on their surface molecules such as the ATP-binding cassette family of transporters (e.g., ABCG2) that pump out chemotherapy compounds out of cells which limits their effects.

3- Detoxification

They have elevated levels of ALDH1 (Aldehyde Dehydrogenase) enzymatic activity. This enzyme breakdown chemotherapy compounds and make them inactive, and therefore, provides cancer stem cells with resistance to chemotherapy.

4- Resistance to Cell Death

Within the cells, there are molecules that control the balance between the survival of a cell and its death.

Cancer stem cells have high expression of the pro-survival BCL-2 protein family members that bind to the pro-apoptotic proteins BCL2-associated-X-protein (BAX) and BCL-2 homologous antagonist killer (BAK) and impair their ability to release cell death signals from the mitochondria.

5-Resistance to DNA Damage

Cancer stem cells have a high DNA damage response and repair which allows them to resist damages that are caused by chemotherapy compounds.

6- The Tumor Microenvironment (TME)

The TME or tumor niche is a highly diverse complex that contains cells such as stromal cells, immune cells, epithelial cells, and a network of extracellular macromolecules.

This complex provides support for cancer stem cells within the extracellular matrix (EC) and plays a key role in promoting their progression into a more malignant and chemotherapy-resistant phenotype.

IV. How Do Cancer Stem Cells Cause Relapse?

Cancer stem cells lead to a more aggressive type of tumors probably due to the emergence of highly selective and chemotherapy-resistant clones of cancer stem cells.

Following chemotherapy, the tumors may disappear, however, after a period, which can last years, a more aggressive and resistant cancer may reappear.

Unfortunately, when this happens, the relapsed cancer is mostly made of resistant cancer cells which makes chemotherapy a difficult choice for treatments.

V. How Is Resistance to Chemotherapy Treated?

Although several drugs are being tested in clinical trials, success has been limited for some drugs due to their toxicity or lack of response [3].

Treatment of advanced cholangiocarcinoma, using CAR-T technology (antibody-based technology) led to toxicity.

Treatment of refractory acute myeloid leukemia metastatic colorectal cancer using monoclonal antibodies led to either limited responses to the therapy or toxicity.

However, other drugs are still being tested in the clinic and the outcome will be known in the future.

Various types of tumors and hematological malignancies are being treated with different types of monoclonal antibodies but the results are not yet available.

A clinical trial that uses a vaccine for the treatment of glioblastoma multiforme has not yet been published.

Conclusion

To prevent resistance and relapse associated with cancer stem cells in patients suffering from aggressive cancers, scientists are investigating the possibility of combining traditional chemotherapy with other types of therapies, such as monoclonal antibodies, and CAR-T technology.