Getting to the heart of the matter in cancer: Novel approaches to targeting cancer stem cells

Abstract

Cancer is one of the leading causes of deaths worldwide. While cancers may initially show good response to chemotherapy or radiotherapy, it is not uncommon for them to recur at a later date. This phenomenon may be explained by the existence of a small population of cancer stem cells, which are inherently resistant to anti-cancer treatment as well as being capable of self-renewal. Therefore, while most of the tumour bulk consisting of cells that are not cancer stem cells respond to treatment, the cancer stem cells remain, leading to disease recurrence. Following this logic, the effective targeting of cancer stem cells holds promise for providing long-term cure in individuals with cancer. Cancer stem cells, like normal stem cells are endowed with mechanisms to protect themselves against a wide range of insults including anti-cancer treatments, such as the enhancement of the DNA damage response and the ability to extrude drugs. It is therefore important to develop new strategies if cancer stem cells are to be eradicated. In this review, we describe the strategies that we have developed to target cancer stem cells. These strategies include the targeting of the histone demethylase jumonji, AT rich interactive domain 1B (JARID1B), which we found to be functionally significant in the maintenance of cancer stem cells. Other strategies being pursued include reprogramming of cancer stem cells and the targeting of a functional cell surface marker of liver cancer stem cells, the aminopeptidase CD13.

Figure 1.

Cancers are made up of cancer stem cells (fluorescent green cells) and differentiated cancer cells (non-fluorescent cells). Conventional cancer treatment is able to eradicate the differentiated cancer cells but not the cancer stem cells. Cancer stem cells cause recurrence at a later date (A). Cancer stem cells demonstrate asymmetrical cell division, giving rise to one fluorescent cancer stem cell and non-fluorescent daughter cell (B). The daughter cell continues to divide multiple times (C and D), to make up the bulk of the cell population (E). While this results in there being only one cancer stem cell, this cell is capable of surviving chemotherapy and regenerating the entire cellular population.

Figure 2.

The mouse xenograft model allows the presence of cancer stem cells to be discerned. This is because only the cancer stem cells are able to form tumours when transplanted into immuno-deficient mice.

Figure 3.

Cancer stem cells can be visualised because they have downregulated 26S proteasome activity. Cells are transfected with a vector coding for a fusion protein consisting of ZsGreen, and the C-terminal degron of the ornithine decarboxylase. Degron directs the destruction of the fluorescent protein by proteasomes in differentiated cancer cells. In cancer stem cells, the fusion protein is not destroyed and the cells are fluorescently labelled.

Figure 4.

Stromal cells can be reprogrammed to inducible pluripotent stem (iPS) cells through the transfection of Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc), or through three miRNAs (miR-200c, miR-302, miR-369). Cancer cells can also be reprogrammed to pluripotent cells, so called inducible pluripotent cancer (iPCs) cells, which have reduced tumour initiating capabilities and increased chemosensitivity.

Figure 5.

CD13 is a functional marker of cancer stem cells, reducing reactive oxygen species (ROS)-induced DNA damage after genotoxic chemo- or radiotherapy, preventing apoptosis. The inhibition of CD13 by the commercially available neutralizing antibody ubenimex results in the increase of ROS, leading to apoptosis.