Cancer dormancy

Last updated
Disseminating cancer cells can proliferate or become dormant depending on the microenvironment and factors such as the ERK/p38 ratio. Cancer Dormancy Diagram.png
Disseminating cancer cells can proliferate or become dormant depending on the microenvironment and factors such as the ERK/p38 ratio.

Dormancy is a stage in cancer progression where the cells cease dividing but survive in a quiescent state while waiting for appropriate environmental conditions to begin proliferation again. [1] Quiescence is the state where cells are not dividing but at arrest in the cell cycle in G0-G1. [1] Dormant cancer cells are thought to be present in early tumor progression, in micrometastases, or left behind in minimal residual disease (MRD) after what was thought to be a successful treatment of the primary tumor. [2]

Contents

Mechanism

Occurrence in cancer

Cancer dormancy is not yet fully understood, but some researchers have performed mathematical modeling to explain the occurrence of cancer dormancy as a characteristic of all migrating tumor cells as part of an evolutionary process of selection and mutation. [3] [4] Recently, scientists from Aga Khan University Pakistan, have extended the studies of encystation in Acanthamoeba to induce dormancy in Prostate cancer cells lines and understanding of the signalling pathways that are involved. [5] This eukaryotic encystation in Acanthamoeba spp., is known to involve a crosstalk between the trophozoite form of the cell and unfavourable microenvoirment that induces it. It is thought that once tumor cells disseminate and begin to migrate to a new site to metastasize, the interaction of the tumor cells with that microenvironment determines whether the cells will proliferate and form metastases or undergo growth arrest and enter cancer dormancy. [1] It is suggested that the disseminated cells choose dormancy when the new environment is not permissive in situations such as cellular stress or a lack of available growth factors. [4] [6] These dormant cells can stay in this state for long periods of time and can be clinically undetectable. [6] [7] However, these cells can be dangerous because they can strike back years after the doctor and patient believe the patient is cured. They can exist in a quiescent state for many years, but the dormancy period can be interrupted to start proliferating uncontrollably and form metastases that cannot be treated. [6] Cancer dormancy is often associated with minimal residual disease (MRD) where some tumor cells are left behind after a treatment and can persist either at the primary tumor site or as disseminated cells that are proliferating or dormant. [1] MRD has been found in a widespread range of cancers including but not limited to: breast, prostate, colon, gastric, colon, pancreatic, head and neck, neuroblastoma, leukemia, melanoma, and others. [1] These cells are often found in the bone marrow, but are also found in other organs and usually indicate poor prognosis for the patient. [1] [6] [8]

One model dubbed DINOMIT (Disjunction, Initiation, Natural selection, Overgrowth, Metastasis, Involution, Transition), proposed by researchers at the Moores Cancer Center at the University of California, San Diego, has vitamin D and calcium in adequate levels playing a crucial role in potentially preventing the onset of cancer (Disjunction) as well as allowing a developed cancer to enter and stay in a weak or fully dormant state (Involution and Transition stages). "It is projected that raising the minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100–150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial." July 2009 Volume 19, Issue 7, Pages 468–483; Vitamin D for Cancer Prevention: Global Perspective; Cedric F. Garland, Dr PH, FACE, Edward D. Gorham, MPH, Sharif B. Mohr, MPH, Frank C. Garland, PhD.

Types of cancer dormancy

Cancer dormancy can refer to two different types: tumor mass dormancy and cellular dormancy.

  1. In tumor mass dormancy, the tumor mass will continue to divide until it is physically limited by size, does not have access to the blood supply, or the immune system acts on it. [1] Here the cells are not completely inactive, but they cannot expand and sit in a balance between proliferation and apoptosis. [1] An emerging Hippo (Hpo) signaling pathway is thought to be responsible for controlling organ size, cell contact inhibition, and tumorigenesis by stopping cell proliferation and promoting cell death. [9] Tumor mass dormancy is also often associated with angiogenic dormancy. This occurs when tumors enter a hypoxic state because they cannot get to blood vessels. If the number of cells still proliferating is balanced by the number dying from no blood supply, the tumor sits in angiogenic dormancy. [1] [10]
  2. Cellular dormancy refers to the cell entering a state of quiescence where growth is arrested in G0-G1 of the cell cycle, and cells are truly inactive and asymptomatic. [1] This is referred to as the dormancy that tumor cells enter when they survive dissemination but cannot adapt immediately to stresses or the new microenvironment. [6] Recently, model pathogenic eukaryotic cell encystation has been linked to cancer cell dormancy, Acanthamoeba spp. were studied for conditions leading to their encystation. These conditions were imposed on prostate cancer cells to induce a state of dormancy from which they could be revived by elimination of the provoking stimuli. [11] Dormant cells might also have different mechanisms that can be used to evade an immune response. [1]

Signaling pathways

Although the mechanism of signaling in cancer dormancy is also poorly understood, there is evidence of many different signaling pathways that are involved in the switch between proliferation and dormancy. The signaling most likely comes from the microenvironment. The switch seems to be mediated by interactions between surface receptors such as uPAR and integrins, mitogenic signaling from the Ras-extracellular signal-regulated kinase (ERK) pathway, and stress induced signaling from the p38 pathway. [6] [12] One example that has been extensively researched is the balance between the ERK pathway and p38 pathway. [1] [4] [6] [7] The ERK pathway has a major role in many cellular processes, but in cancer dormancy it is thought to be involved in mitogenic signaling that results in heightened proliferation. [6] [13] The p38 pathway is thought to be involved in cell cycle arrest and induction of apoptosis. [6] Thus, a higher ERK/p38 ratio usually indicates proliferation and a lower ratio causes dormancy. [4] [14]

Clinical and therapeutic importance

The push for understanding the mechanism of cancer dormancy is important for several clinical reasons. These dormant cancer cells are often untreatable due to drug resistance. These cells are usually resistant to chemotherapy because they are not dividing, and chemotherapy best targets rapidly diving cells. [1] [7] [15] [16]

  1. An idea for a therapeutic strategy is to cause cancer cells to be induced or maintained in a dormant state. By inducing normally untreatable malignant cells into growth arrest, the patient would be able to survive in a chronic asymptomatic condition. [7] This could be accomplished by finding the correct ratio of mitogenic signals like ERK to p38. [7] However, even though a cell can remain dormant for a long period of time, there is always the risk of interrupted dormancy leading to metastasis by even the smallest change in a signaling network. [6] Another therapeutic strategy is to develop methods to knock out dormant cells completely.
  2. By targeting the mechanisms behind dormant cell survival and how they acquire drug resistance, it might be possible to induce these dormant cells to their death. [1] [16]
  3. Finally, it is hoped that understanding the mechanism of dormancy will allow researchers to find potential markers of dormancy that might contribute to determining the prognosis of the patient. [2] [6]

Remaining questions

There are many questions that remain to be answered in the quest for understanding cancer dormancy more fully. Some of these include:

Finally, it is important for scientists to use models that can more accurately model the stage of cancer dormancy to discover its mechanism. By more fully understanding the mechanism of cancer dormancy, it will be possible to find new therapeutic strategies to target these dormant cancer cells. It might be that the body is not completely rid of cancer cells in the way that might be considered "cured" by complete elimination, but it is an alternative "operational cure" by which the patient is in control of a chronic disease so that they will eventually die with their cancer instead of from it. [9]

Related Research Articles

<span class="mw-page-title-main">Oncogene</span> Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

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.

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a mitogen is that it triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), leading to mitosis.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

<span class="mw-page-title-main">Indole-3-carbinol</span> Chemical compound

Indole-3-carbinol (C9H9NO), sometimes referred to as I3C, is produced by the breakdown of the glucosinolate glucobrassicin, which can be found at relatively high levels in cruciferous vegetables such as broccoli, cabbage, cauliflower, brussels sprouts, collard greens and kale. It is also available in dietary supplements. Indole-3-carbinol is the subject of on-going biomedical research into its possible anticarcinogenic, antioxidant, and anti-atherogenic effects. Research on indole-3-carbinol has been conducted primarily using laboratory animals and cultured cells. Limited and inconclusive human studies have been reported. A recent review of the biomedical research literature found that "evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent" and "larger randomized controlled trials are needed" to determine if supplemental indole-3-carbinol has health benefits.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

<span class="mw-page-title-main">Subventricular zone</span> Region outside each lateral ventricle of the brain

The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).

<span class="mw-page-title-main">Cyclin D</span>

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

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

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">Sigma-2 receptor</span> Protein-coding gene in the species Homo sapiens

The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as cancer and neurological diseases. It is currently under investigation for its potential diagnostic and therapeutic uses.

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">MAP2K5</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the MAP2K5 gene.

<span class="mw-page-title-main">DLC1</span> Protein-coding gene in the species Homo sapiens

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

A431 cells are a model human cell line used in biomedical research.

<span class="mw-page-title-main">Cinobufagin</span> Chemical compound

Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad Bufo gargarizans. It has similar effects to digitalis and is used in traditional Chinese medicine.

<span class="mw-page-title-main">The Hallmarks of Cancer</span> 2000 paper by Hanahan and Weinberg

The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.

<span class="mw-page-title-main">Withaferin A</span> Chemical compound

Withaferin A is a steroidal lactone, derived from Acnistus arborescens, Withania somnifera and other members of family Solanaceae. It has been traditionally used in ayurvedic medicine. It is the first member of the withanolide class of ergostane type product to be discovered. This natural product has wide range of pharmacological activities including cardioprotective, anti-inflammatory, immuno-modulatory, anti-angiogenesis, anti-metastasis and anti-carcinogenic properties.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Aguirre-Ghiso, Julio A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature. 7, 834 – 846.
  2. 1 2 Paez David, Labonte Melissa J., Bohanes Pierre, Zhang Wu, Benhanim Leonor, Ning Yan, Wakatsuki Takeru, Loupakis Fotios and Lenz Heinz-Josef. (2012). Cancer Dormancy: A Model of Early Dissemination and Late Cancer Recurrence. Clin Cancer Res. 18, 645.
  3. ↑ Klein C. A. and Holzel D. (2006). Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle. 5:16, 1788–1798.
  4. 1 2 3 4 5 6 7 Wikman Harriet, Vassella Robert and Pantel Klaus. (2008). Cancer micrometastasis and tumor dormancy. APMIS. 116, 754 – 770.
  5. ↑ Baig AM, Khan NA, Abbas F. Eukaryotic cell encystation and cancer cell dormancy: is a greater devil veiled in the details of a lesser evil? Cancer Biol. Med. 2015 Mar;12(1):64-7. doi: 10.7497/j.ISSN 2095-3941.2014.0028.
  6. 1 2 3 4 5 6 7 8 9 10 11 Ranganathan Aparna C., Adam Alejandro P. and Aguirre-Ghiso Julio A. (2006). Opposing Roles of Mitogenic and Stress Signaling Pathways in the Inductions of Cancer Dormancy. Cell Cycle. 5:16, 1799–1807.
  7. 1 2 3 4 5 Aguirre-Ghiso, Julio A. (2006). The Problem of Cancer Dormancy: Understanding the Basic Mechanisms and Identifying Therapeutic Opportunities. Cell Cycle. 5:16, 1740–1743.
  8. ↑ Braun S., Vogl F. D., Naume B., Janni W., Osborne M. P., Coombes R. C., Schlimok G., Diel I. J., Gerber, B., Gebauer G., Pierga J. Y., Martha C., Oruzio D., Wiedswang G., Solomayer E. F., Kundt G., Strobl B., Fehm T., Wong G. Y., Bliss J., Vincent-Salomon, A. and Pantel, K. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 353, 793 – 802.
  9. 1 2 Uhr Jonathan W. and Pantel Klaus. (2011). Controversies in clinical cancer dormancy. PNAS. 108:30, 12396–12400.
  10. ↑ Naumov G.N., Akslen L.A., and Folkman J. (2006). Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle. 5:16, 1779–1787.
  11. ↑ Baig AM, Khan NA, Abbas F. Eukaryotic cell encystation and cancer cell dormancy: Is a greater devil veiled in the details of a lesser evil? Cancer Biol
  12. ↑ Aguirre-Ghiso J. A., Liu D., Mignatti A., Kovalski K., and Ossowski L. (2001). Urokinase receptor and fibronectin regulate the ERK (MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Bio Cell. 12, 863 – 879.
  13. ↑ Aguirre-Ghiso J. A., Estrada Y., Liu D., and Ossowski L. (2003). ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res. 63, 1684–1695.
  14. ↑ Aguirre-Ghiso J. A., Ossowski L., and Rosenbaum, S.K. (2004). Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res. 64:20, 7336 – 7345.
  15. ↑ Naumov G.N., Townson J.L., MacDonald I. C., Wilson S.M., Bramwell V. H., Groom A. C. and Chambers A. F. (2003). Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat. 82:3, 199 – 206.
  16. 1 2 Ranganathan A. C., Zhang L., Adam A. P., Aguirre-Ghiso J. A. (2006). Functional coupling of p38-induced upregulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 66, 1702–1711.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.