Breast cancer stem cell

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Breast cancer is the most prevalent type of cancer among women globally, with 685,000 deaths recorded worldwide in 2020. [1] The most commonly used treatment methods for breast cancer include surgery, radiotherapy and chemotherapy. [2] Some of these treated patients experience disease relapse and metastasis. The aggressive progression and recurrence of this disease has been attributed the presence of a subset of tumor cells known as breast cancer stem cells (BCSCs). These cells possess the abilities of self-renewal and tumor initiation, allowing them to be drivers of metastases and tumor growth. [3] The microenvironment in which these cells reside is filled with residential inflammatory cells that provide the needed signaling cues for BCSC-mediated self-renewal and survival. [4] The production of cytokines allows these cells to escape from the primary tumor and travel through the circulation to distant organs, commencing the process of metastasis. [5] Due to their significant role in driving disease progression, BCSCs represent a new target by which to treat the tumor at the source of metastasis.

Contents

Origins and Characteristics

Cancer stem cells in breast tumors were first discovered in 2003. [6] There are different theories exist on the origins of these cells. There are findings that indicates that normal cells undergo mutations which result in their transformation into BCSCs, [7] while there are also studies which concluded that these cells come from the misplacement of somatic stem cells de novo. [8]

The expression of key surface markers have been used to identify and isolate BCSCs. Three key proteins have been deemed as markers for BCSCs: CD44, CD24 and aldehyde dehydrogenase (ALDH). [9] CD44, a cell surface glycoprotein, plays a crucial role in the adhesion, migration and invasion of breast cancer cells. [10] In addition to its ability to promote proliferation and metastasis, the interaction of this protein with osteopontin hastens tumor progression. [11] ALDH, a family of enzymes that oxidizes intracellular aldehydes and retinol, aids in the differentiation of stem cells. [12] Research has shown that BCSCs are positive for both CD44 and ALDH, while negative for CD24. [13]

Signaling Pathways and Molecules

The tumor niche in which these BCSCs reside supports their growth and self-renewal. This microenvironment provides these cells with a physical anchoring site, a process mediated by adhesion molecules, components of the extracellular matrix (ECM) and factors secreted by stromal cells. [14] Such as the interactions between hyaluronic acid (HA) and CD44 stimulate the activation of other pathways that promote tumor malignancy such as Nanog, HER2 and NF-κβ. [15] The activation of these pathways result in increased proliferation, invasion and migration of BCSCs. As a result, primary breast cancer tumors quickly form metastases in distant sites. Both the epithelial-to-mesenchymal transition (EMT) and the mesenchymal-to-epithelial transition (MET) are key components of driving this metastasis process. BCSCs undergo both of these processes as they escape from the primary tumor site, enter the bloodstream and home to a new organ site to initiate tumor growth. Over the course of this process, there is an upregulation of growth factors, which in turn activate and deactivate mesenchymal and epithelial transcription factors. [16] The combination of these factors provides the signaling cues needed by BCSCs to survive, grow and proliferate.

Pathways that play key roles in embryonic development and adult tissue homeostasis have also been implicated in driving the phenotype of BCSCs. Dysregulation of the Notch and Hedgehog pathways, which regulate normal stem cell differentiation and self-renewal, is one such example. [17] Both of these pathways have been shown to be upregulated in breast cancer. Some early work has shown that activation of these pathways can also be correlated to the resistance of BCSCs to therapy. [18]

Breast Cancer Metabolism

Breast cancer stem cells establish their cell identity by expressing unique pattern of proteins and surface markers as fingerprints. Accordingly, breast cancer stem cells have distinctive metabolic properties to sustain their stemness and promote cancer progression. [19] While reduced ROS Level promotes radioresistance and EMT phenotype of cancer stem cells, Notch signaling interacts with cellular metabolism to promote breast cancer stem cell. [19]

Therapeutic Implications

Both pre-clinical and clinical studies have shown a correlation between BCSCs and metastasis. For example, it has been shown that CD44+/CD24- tumor cells in the breast primary tumors associated with the presence of distance metastases. [20] In addition, in vitro assays validated that these cells displayed increased motility and invasiveness. [21] There have been indications of the link between chemoresistance of CSCs and metastasis. Pleural metastases from breast cancer patients were enriched with CD44+/CD24- cells, indicative of a higher enrichment of BCSCs in these resistant tumors. [22] Therapy resistance of BCSCs is mediated by a host of mechanisms, which include ATP-binding cassette transporters, ALDH activity and reactive oxygen species scavenging. [23] As a result, these tumors become difficult to treatment by conventional methods such as chemotherapy. This has spurred the search for new drug delivery platforms that can target BCSCs and the niche in which these cells reside. A breakdown of this biological framework and structure would provide an alternate means by which to treat this disease.

Related Research Articles

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Cancer stem cell</span> Cancer cells with features of normal cells

Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

<span class="mw-page-title-main">CD44</span> Cell-surface glycoprotein

The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.

<span class="mw-page-title-main">CD24</span> Mammalian protein found in Homo sapiens

Signal transducer CD24 also known as cluster of differentiation 24 or heat stable antigen CD24 (HSA) is a protein that in humans is encoded by the CD24 gene. CD24 is a cell adhesion molecule.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">Mucin 4</span> Protein-coding gene in the species Homo sapiens

Mucin-4 (MUC-4) is a mucin protein that in humans is encoded by the MUC4 gene. Like other mucins, MUC-4 is a high-molecular weight glycoprotein.

<span class="mw-page-title-main">RhoC</span> Protein-coding gene in the species Homo sapiens

RhoC is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC.

<span class="mw-page-title-main">Hyaluronan-mediated motility receptor</span> Protein-coding gene in the species Homo sapiens

Hyaluronan-mediated motility receptor (HMMR), also known as RHAMM (Receptor for Hyaluronan Mediated Motility) is a protein which in humans is encoded by the HMMR gene. RHAMM recently has been also designated CD168 (cluster of differentiation 168).

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

<span class="mw-page-title-main">MTA3</span> Protein-coding gene in the species Homo sapiens

Metastasis-associated protein MTA3 is a protein that in humans is encoded by the MTA3 gene. MTA3 protein localizes in the nucleus as well as in other cellular compartments MTA3 is a component of the nucleosome remodeling and deacetylate (NuRD) complex and participates in gene expression. The expression pattern of MTA3 is opposite to that of MTA1 and MTA2 during mammary gland tumorigenesis. However, MTA3 is also overexpressed in a variety of human cancers.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

<span class="mw-page-title-main">Joan Massagué</span> Spanish biologist

Joan Massagué, is a Spanish biologist and the current director of the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center. He is also an internationally recognized leader in the study of both cancer metastasis and growth factors that regulate cell behavior, as well as a professor at the Weill Cornell Graduate School of Medical Sciences.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Migration inducting gene 7 is a gene that corresponds to a cysteine-rich protein localized to the cell membrane and cytoplasm. It is the first-in-class of novel proteins translated from what are thought to be long Non-coding RNAs.

Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be caused by genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.

Recurrent cancer is any form of cancer that has returned or recurred when a fraction of primary tumor cells evade the effects of treatment and survive in small spaces that are undetectable by diagnostic tests. The initial tumor may become the site of cancer’s return or it may spread to another part of the body. These surviving cells accumulate various genetic changes over time, eventually producing a new tumor cell. It can take up to weeks, months, or even years for cancer to return. Following surgery and/or chemotherapy or radiotherapy, certain tumor cells may persist and develop resistance to treatment and eventually develop into new tumors. Age, sex, cancer type, treatment duration, stage of advancement, and grade of original tumor are some of the factors that determine the rate of cancer recurrence. If recurrent cancer has already moved to other body parts or has developed chemo-resistance then it may be more aggressive than original cancer. In general, the severity of cancer increases with a shorter duration of time between initial treatment and its return.

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