Breast Cancer Stem Cells Research Paper

Breast Cancer Stem Cells Research Paper

Stem cells are among the leading areas of active research. This interest is due to the stem cell’s ability to replicate endlessly and give rise to various tissues originating from the three germ layers. Stem cell therapy gets applied in fields such as the definitive treatment of genetic diseases such as sickle disease and various cancers like leukemia with excellent results. Stem cells reside in almost all actively replicating organs, such as the gut, bone marrow, and breast tissues. Even more, there has been a steady but gradual acceptance of the origin of cancer from mutations that affect stem cells. As such, this research paper shall assess the breast, highlighting the evidence for stem cells in it, delve into proof for stem cells in breast cancer, and its implications. Finally, address the novel therapies aimed at eliminating stem cells for better outcomes in breast cancer patients.

The mammary gland is a structurally dynamic organ under tight hormonal control based on the woman’s age, menstrual cycle, and reproductive status. Hormones active in the breast include estrogen and progesterone during development and the normal menstrual cycle. Other hormones play a role in milk production, including follicle-stimulating hormone (FSH), prolactin, oxytocin, and human placental lactogen (HPL (Lawson & Glenn, 2017). Furthermore, the breast’s structure is in constant flux under the action of the hormones highlighted above. Its structure gets divided into parenchyma and stroma. Here, the latter comprises loose connective tissue, while the former constitutes epithelial and myoepithelial cells. The breast gets divided into lobules and ducts lined by the luminal epithelial cells. In contrast, the myoepithelial cells form an outer layer that secretes the basement membrane to separate the stroma and parenchyma.

There has been speculation about the existence of mammary stem cells based on several lines of proof. Examples here include the expansion and reproductive ability of the breast during puberty and a woman’s reproductive cycles. Further evidence consists of the existence of two different cell lines from a common progenitor and the fact that cells shed into the lumen get continuously replaced. New evidence for stem cells in healthy breast tissue has resulted in transplantation studies in mouse models (Clark & Fuller, 2006). Additionally, in mice in different stages of development, the epithelium can generate functional mammary epithelium with its various constituents, such as ducts, lobules, and myoepithelium. Furthermore, as earlier suspected, these stem cells follow a defined hierarchical model with three different outcomes. Here cells can regenerate the entire epithelial compartment and two downstream progenitors that are more committed and give rise to either secretory lobules or the branching ducts.

The above process is highly regulated, with only stem cells retaining the indefinite replicating ability since the downstream progenitors differentiate terminally. Stem cells can divide asymmetrically by producing one copy of themselves and another of the transit-amplifying progenitor. Thus, a cell creates copies of itself, maintaining the ability indefinitely continuously. As such, the isolation of stem cells for propagation to other sites becomes challenging. Majorly the challenge comes from the lack of a system that would allow the cells to be transported in the undifferentiated state. This challenge limits a field of experimental research that would enable the implantation of stem cells with the potential to give rise to entire organs (Cariati & Purushotham, 2007). Furthermore, recognizing a stem cell compartment in healthy breast tissues has led to the theory of its existence in tumor cells (Cariati & Purushotham, 2007). Since these stem cells are likely the source of cancer in healthy tissues, it becomes an exciting area of research. By extension, the healthy epithelial stem cells would give rise to cancer stem cells by accumulating mutations over time, eventually producing tumor cells.

Cancer develops as a result of two factors: genetic instability and environmental factors. Environmental factors include radiation, carcinogenic compounds such as asbestos and cigarette smoke, and oncogenic viruses such as human papillomavirus. Additionally, cancers often arise in organs that need continuous replication, such as the gut, blood, and skin. These organs have large stem cell compartments due to this requirement and thus are a brooding ground for the growth of cancer stem cells. As a result, cancer stem cells may arise in various methods. The niche cells comprise the normal stem cell micro-environment and control the ability of stem cells to regenerate by using paracrine signals (Clark & Fuller, 2006). Expansion of this stem cell niche causes a corresponding growth of the cancer stem cells, which get derived from healthy stem cells. Consequently, these cancer stem cells then acquire mutations that enable them to control alternative niche cells that give them signals to self-renew, thus serving a vicious cycle.

Furthermore, cancer stem cells undergo genetic alterations that make them niche independent in that they no longer need these growth signals from niche cells to replicate. Another method that gets observed is the gain of mutations in the transit-amplifying progenitor stem cells that give them the ability to continuously self-renew, akin to stem cells. Of interest is that some of the typical variations of leukemia, such as the 8:21 translocation in acute myeloid leukemia, have been noted in up to eight percent of healthy stem cells despite these cells normally dividing (Cariati & Purushotham, 2007). Even more, cancer stem cells, like healthy stem cells, are also resistant to extreme conditions such as low oxygen tension and considerable shifts in the ph. They are also resistant to DNA, and thus the effect of cytotoxic drugs is diminished in them. Additionally, the cancer stem cells, like healthy stem cells, do not divide rapidly and are resistant to drugs that target cells with high mitotic indexes. The cells also function like healthy cells, providing a continuous supply of tumor cells.

Tumors display extensive heterogeneity, with only a few cell lines able to form colonies. This fact supports the existence of stem cells, as only a few tumor lines can reproduce and spread extensively. Thus, theories to explain the origins of cancer stem cells in solid tumors like the breast have been narrowed down to two. One hypothesis states that every tumor cell can proliferate, thus creating new tumors. However, despite this intrinsic ability to replicate, only a small subset of cells can complete all the necessary steps. The second hypothesis postulates that only a small subset of cells can proliferate and form new tumors. These few cells, however, can do this very efficiently (Cariati & Purushotham, 2007). Such cells display various antigens on their surface; thus, they and their daughter lines can be identified. Here, markers include antigens such as CD44+/CD24- in breast tissues, which have a ten to fifty-fold increase in the ability to form tumors in mouse models. Furthermore, as earlier highlighted, the pathways used to maintain healthy stem cells are usually mutated in cancers, especially the signaling pathway.

Stem cell therapy in cancer works to replace damaged cells in the body. These cells may have become damaged by the disease process itself, such as leukemia in the bone marrow or the therapy aimed at treatment of the disease process. For example, many of the drugs used to treat cancer have cytotoxic and bone marrow suppression properties as they inadvertently also kill the healthy cells in the marrow (Chari, 2008). Such drugs eradicate vast populations of cells, and stem cells then get used to replacing the destroyed healthy cells. Stem cells have an intrinsic property that draws them toward sites of inflammation. In treating diseases such as sickle cells, retroviruses that can integrate themselves into the host DNA and use it to produce copies of themselves are used to deliver the necessary genes to cells (Esmaeilzadeh & Farshbaf, 2015). These carrier viruses are akin to Trojan horses and have become genetically modified to include genes that code for the missing compound in the diseased individual. Furthermore, they then harness the cell’s apparatus to make more copies of itself, providing the needed compound such as glutamic acid in sickle cell diseases.

The presence of cancer stem cells has implications for cancer treatment, as the current viewpoint on the efficacy of cancer drugs is very much based on the proportion of tumor cells killed by the drug regimen. However, most therapies kill only the end differentiated cells while leaving cancer stem cells intact, therefore leaving a loophole for recurrence (Cariati & Purushotham, 2007). Future regimens will have to get developed after testing and characterizing them on tissue samples to screen for any innate resistance within the tumor stem cells. As earlier highlighted, tumor lines are very heterogeneous, so based on the markers displayed by the stem cells, prognostication of patients will be feasible. Care can become personalized, with the most invasive subtypes receiving the most intensive therapies. Stem cells are also responsible for developing multidrug-resistant strains of tumors, so sensitizing the cancer stem cells to existing regimens may be a way to modulate this.

The mammary gland is a dynamic organ made up of different cell types and under the control of various hormones with substantial proof for the existence of stem cells within solid tissue, including the breast. Such developments led to the search for the existence of cancer stem cells within tumors, with these often being an endless source of tumor cells. The proof has been in the form of transplantation studies in mouse models and lineage analysis based on the surface antigens displayed by these tumor cells. Little became understood in the scale of cancer stem cells, leaving much room for research into this. The future is indeed tantalizing with the possibility of more tailored drug regimens in the future, primarily geared towards eliminating cancer stem cells.

References

Cariati, M., & Purushotham, A. (2007). Stem cells and breast cancer. Retrieved from https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2559.2007.02895.x

Chari, R. (2008). Targeted cancer therapy: Conferring specificity to cytotoxic drugs. Retrieved from https://pubs.acs.org/doi/abs/10.1021/ar700108g

Clark, M., & Fuller, M. (2006). Stem cells and cancer: The two faces of Eve. Retrieved from https://www.sciencedirect.com/science/article/pii/S0092867406003126

Esmaeilzadeh, A., & Farshbaf, A. (2015). Mesenchymal stem cell as a vector for gene and cell therapy strategies. Studies on Stem Cells Research and Therapy, 1(1), 017-018.

Lawson, J., & Glenn, W. (2017). Multiple oncogenic viruses are present in human breast tissues before the development of virus-associated breast cancer. Infectious Agents and Cancer, 12(1).