The Hallmarks of Cancer

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The ability to invade surrounding tissue and metastasise is a hallmark of cancer. Melanoma infiltrating the brain.jpg
The ability to invade surrounding tissue and metastasise is a hallmark of cancer.

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 . [1]

Contents

These hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. In addition to cancer cells, tumors exhibit another dimension of complexity: they incorporate a community of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the “tumor microenvironment.” Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. [1]

In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways and (2) evasion of the immune system, and two enabling characteristics: (1) genome instability, and (2) inflammation. [2]

List of hallmarks

Signalling pathways are deregulated in cancer. Hanahan and Weinberg compared the signalling pathways to electronic circuits where transistors are replaced by proteins. The prototypical Ras pathway starts with an extracellular signal from growth factors (such as TGF-a). Other major extracellular signals are anti-growth factors (such as TGF-b), death factors (such as FASL), cytokines (such as IL-3/6)and survival factors (such as IGF1). Proteins inside the cell control the cell cycle, monitor for DNA damage and other abnormalities, and trigger cell suicide (apoptosis). Hanahan and Weinberg's signal pathway illustration is at Cell 100:59 Signal transduction v1.png
Signalling pathways are deregulated in cancer. Hanahan and Weinberg compared the signalling pathways to electronic circuits where transistors are replaced by proteins. The prototypical Ras pathway starts with an extracellular signal from growth factors (such as TGF-α). Other major extracellular signals are anti-growth factors (such as TGF-β), death factors (such as FASL), cytokines (such as IL-3/6)and survival factors (such as IGF1). Proteins inside the cell control the cell cycle, monitor for DNA damage and other abnormalities, and trigger cell suicide (apoptosis). Hanahan and Weinberg's signal pathway illustration is at Cell 100:59

Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis).

Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit programmed cell death (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.

All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical protein must malfunction in each of those mechanisms. These proteins become non-functional or malfunctioning when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, which Hanahan and Weinberg refer to as hallmarks.

Summary
CapabilitySimple analogy
Self-sufficiency in growth signals"accelerator pedal stuck on"
Insensitivity to anti-growth signals"brakes don't work"
Evading apoptosis won't die when the body normally would kill the defective cell
Limitless replicative potentialinfinite generations of descendants
Sustained angiogenesis telling the body to give it a blood supply
Tissue invasion and metastasis migrating and spreading to other organs and tissues

Self-sufficiency in growth signals

Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply.

Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signaling; by permanently activating the signaling pathways that respond to these signals; or by destroying 'off switches' that prevents excessive growth from these signals (negative feedback). In addition, cell division in normal, non-cancerous cells is tightly controlled. In cancer cells, these processes are deregulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor. [4] [5]

Insensitivity to anti-growth signals

Cancer cells are generally resistant to growth-preventing signals from their neighbours.
The cell cycle clock. Cells do not divide in G0 and are quiescent. After receiving growth factor signals, they prepare for division by entering G1, where everything within the cell except DNA is doubled. This doubling includes the size of the cell. The next phase of the cell cycle is S (synthesis) phase. It is the cell cycle phase where the chromosomes (DNA) are duplicated in preparation for cellular division. The transition from G1 to S is a checkpoint. If the cell has damaged DNA or is expressing oncogenes or other inappropriate proteins, specialized checkpoint proteins, tumor suppressors such as p53 or pRB, will interrupt the transition to S phase until the damage is repaired. If the damage cannot be repaired, the cell will initiate apoptosis, often referred to as cellular suicide, which is programmed cell death. If the tumor suppressor genes incur loss-of-function mutations or are knocked out, the damaged cell can continue to divide unchecked - one of the hallmarks of cancer. Cell Cycle 2-2.svg
The cell cycle clock. Cells do not divide in G0 and are quiescent. After receiving growth factor signals, they prepare for division by entering G1, where everything within the cell except DNA is doubled. This doubling includes the size of the cell. The next phase of the cell cycle is S (synthesis) phase. It is the cell cycle phase where the chromosomes (DNA) are duplicated in preparation for cellular division. The transition from G1 to S is a checkpoint. If the cell has damaged DNA or is expressing oncogenes or other inappropriate proteins, specialized checkpoint proteins, tumor suppressors such as p53 or pRB, will interrupt the transition to S phase until the damage is repaired. If the damage cannot be repaired, the cell will initiate apoptosis, often referred to as cellular suicide, which is programmed cell death. If the tumor suppressor genes incur loss-of-function mutations or are knocked out, the damaged cell can continue to divide unchecked – one of the hallmarks of cancer.
The hallmarks of cancer. Hallmarks of cancer.svg
The hallmarks of cancer.

To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are orchestrated by proteins encoded by tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not (when the DNA is damaged, for example). In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division, even when the cell has severe abnormalities. One of the most significant tumor suppressors is known as p53. It plays such a critical role in regulation of cell division and cell death that in 70% of cancer cells p53 is found either mutated or functionally inactivated. Often times tumors can not form successfully without deactivating critical tumor suppressors like p53. [6] Another way cells prevent over-division is that normal cells will also stop dividing when the cells fill up the space they are in and touch other cells; known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings. [4] [7]

Evading programmed cell death

Apoptosis is a form of programmed cell death (cell suicide), the mechanism by which cells are programmed to die in the event they become damaged. Cancer cells are characteristically able to bypass this mechanism.

Cells have the ability to 'self-destruct'; a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability; even though cells may become grossly abnormal, they do not undergo apoptosis. The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. This means that proper signaling cannot occur, thus apoptosis cannot activate. They may also have defects in the downstream signaling itself, or the proteins involved in apoptosis, each of which will also prevent proper apoptosis. [4] [8]

Limitless replicative potential

Non-cancer cells die after a certain number of divisions. Mutant cells escape this limit and are apparently capable of indefinite growth and division (immortality). But those immortal cells have damaged chromosomes, which can become cancerous.

Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide (senescence), or die (crisis). The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes (telomerase) to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence. [4] [9]

Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60–70 doublings, at which point they reach a stage of senescence.

This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10−7) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.

The counting device for cell doublings is the telomere, which decreases in size (loses nucleotides at the ends of chromosomes) during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres. [10]

Sustained angiogenesis

Angiogenesis is the process by which new blood vessels are formed. Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients.

Normal tissues of the body have blood vessels running through them that deliver oxygen from the lungs. Cells must be close to the blood vessels to get enough oxygen for them to survive. New blood vessels are formed during the development of embryos, during wound repair and during the female reproductive cycle. An expanding tumor requires new blood vessels to deliver adequate oxygen to the cancer cells, and thus exploits these normal physiological processes for its benefit. To do this, the cancer cells acquire the ability to orchestrate production of new vasculature by activating the 'angiogenic switch'. In doing so, they control non-cancerous cells that are present in the tumor that can form blood vessels by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote blood vessel formation. [4] [11] Normal development and equilibrium depend on the physiological process of angiogenesis, which is strictly controlled. It assists in the development of a functioning circulatory network during embryogenesis and is essential for repairing damaged tissue and wounds in adulthood. In order to ensure appropriate vascular growth without excessive or inadequate blood vessel production, pro-angiogenic and anti-angiogenic factors usually interact constantly to maintain angiogenesis in balance. This equilibrium becomes disrupted in cancer, as tumors are able to use and control the host's vascular system for their own advancement thanks to the angiogenic switch, a theory initially proposed by Folkman in 1971. [12] This change demonstrates how cancers can take over healthy cellular functions and transform them into malignant ones.

Our knowledge of the complexity of this network has grown as more molecules, including as platelet-derived growth factor (PDGF) and angiopoietins, have been linked to the angiogenic process in addition to VEGF and bFGF. Additionally, the importance of the tumor microenvironment in maintaining angiogenesis is becoming more well acknowledged. To enhance the angiogenic signal, for example, mesenchymal stem cells and cancer-associated fibroblasts (CAFs) in the tumor stroma may release pro-angiogenic cytokines. Another strong inducer of angiogenesis is hypoxia, or oxygen deprivation in the tumor core, which stabilizes hypoxia-inducible factor-1α (HIF-1α), a transcription factor that promotes the production of VEGF and other angiogenic mediators. [13]

The function of exosomes, which are tiny extracellular vesicles released by tumor cells, in promoting angiogenesis has also been brought to light by recent studies. [14] These exosomes involve microRNAs and angiogenic proteins that alter endothelial cell activity, promoting tube formation, migration, and proliferation. Developing an understanding of these new processes opens up new therapeutic intervention options and offers important insights into the complex relationships between variables influencing tumor angiogenesis.

Tissue invasion and metastasis

Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread ( metastasize ) to distant body parts.

One of the most well known properties of cancer cells is their ability to invade neighboring tissues. It is what dictates whether the tumor is benign or malignant, and is the property which enables their dissemination around the body. The cancer cells have to undergo a multitude of changes in order for them to acquire the ability to metastasize, in a multistep process that starts with local invasion of the cells into the surrounding tissues. They then have to invade blood vessels, survive in the harsh environment of the circulatory system, exit this system and then start dividing in the new tissue. [4] [15]

Local Tissue Invasion

Epithelial-Mesenchymal Transition (EMT)

Epithelial-to-mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and cell-cell adhesion properties and acquire mesenchymal traits, such as enhanced motility and invasiveness. This transformation plays a critical for various physiological processes, such as embryonic development, wound healing, and tissue regeneration. However, in cancer, EMT is often hijacked to promote tumor progression and metastasis. During EMT, epithelial markers like E-cadherin are downregulated, while mesenchymal markers such as N-cadherin and vimentin are upregulated. This change enables cancer cells to detach from the primary tumor, invade surrounding tissues, and ultimately spread to distant locations in the body by entering the bloodstream or lymphatic pathways. [16]

Cancer cells undergo several changes that enable them to invade surrounding tissues. A primary mechanism is the downregulation of E-cadherin which is an epithelial adhesion molecule that helps maintain cell-cell adhesion. Loss of E-cadherin reduces cellular cohesion, allowing cancer cells to detach from the primary tumor. This is a hallmark of epithelial-to-mesenchymal transition (EMT), during which cancer cells acquire mesenchymal traits, such as increased motility and invasiveness. [17] [18]

Degradation of the Extracellular Matrix (ECM)

To invade nearby tissues, cancer cells cells secrete enzymes such as matrix matalloproteinases (mmps) that degrade the ECM and basement membrane. [19] This breakdown creates pathways for cancel cells to migrate and infiltrate new areas.

Tumor Microenvironment

The tumor microenvironment, composed of stromal cells, immune cells and singaling molecules, supports invasion by creating good and favorable conditions for tumor cell migration. [20] For example, cancer- associated fibroblasts (CAFS) produce substances that remodel the ECM and promote cancer progression. [20]

Tumor Metastasis and Roles of Biomarkers

Intravastation (Mechanism)

Intravasation is the process where tumor cells enter blood or lymphatic blood vessels, allowing them to travel to distant parts of the body. This step is important in the metastatic journey as it enables tumor cells to leave their original site and circulate through the body. pro- angiogenic factors like VEGF, [21] along with interactions between cancer calls and the vessel walls, make it easier for tumor cells to penetrate into the bloodstream or lymphatic system. By gaining access to these transport networks, cancer cells increase their ability to spread and form new tumors in distant tissues.

Circulating Tumor cells (CTCs) (Mechanism)

When cancer cells enter the bloodstream, they are known as circulating tumor cells (CTCs). To protect themselves from being detected and destroyed by the immune system, these cells often group together in clusters or cover themselves with platelets. This protective strategy increases their chances of survival and makes it easier for them to spread to other parts of the body. [22]

Extravasation and Colonization (Mechanism)

Extravasation occurs when circulating tumor cells leave the bloodstream and invade new tissues, guided by molecules like integrins. [23] Integrins help the cells attach and move into their new environment. Once settled, cancer cells form a metastatic niche that helps them grow and establish a new tumor in a new location.

E-cadherin (Biomarker) (Mechanism)

E-cadherin is an epithelial adhesion protein that plays an essential role in maintaining tissue structure by facilitating cell-cell adhesion. Its down regulation is a major feature of EMT transition which is a process that is important for cancer metastasis. The loss of E-cadherin disrupts cellular adhesion, allowing tumor cells to detach from the primary site and invade surrounding tissues. This type of suppression is often mediated by EMT transcription factors such as ZEB1, Snail, and Twist, is then repress E-cadherin gene expression. Furthermore, when E-cadherin is reduced, it facilitates interactions with the extracellular matrix (ECM) which in then enhances the ability of cancer cells to migrate and invade surrounding tissues. By promoting these interactions, E-cadherin is able to support cellular motility and aid tumor cells navigate the tissue structures which drives metastasis. [3] [5] Research emphasizes E-cadherin as a major biomarker in metastatic cancers such as breast and colorectal cancers. Low levels of E-cadherin are often linked to poor clinical outcomes, therapy resistance and aggressive tumor phenotypes. [6]

Updates

In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation." [2]

Emerging Hallmarks

Deregulated metabolism

Most cancer cells use alternative metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, [24] [25] but only now gaining renewed research interest. [26] Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration (oxidation of pyruvate, the citric acid cycle, and the electron transport chain). Instead of completely oxidizing glucose to produce as much ATP as possible, cancer cells would rather convert pyruvate into the building blocks for more cells. In fact, the low ATP:ADP ratio caused by this effect likely contributes to the deactivation of mitochondria. Mitochondrial membrane potential is hyperpolarized to prevent voltage-sensitive permeability transition pores (PTP) from triggering of apoptosis. [27] [28] There are many works that sustain that cancer is a metabolic disease. [29] [30] This research approach has contributed to a better understanding of cancer metabolism, providing a foundation for developing new, metabolism-targeted therapies that could complement existing treatments and help overcome drug resistance in various cancers. [31] The ketogenic diet is being investigated as an adjuvant therapy for some cancers, [32] [33] [34] including glioma, [35] [36] because of cancer's inefficiency in metabolizing ketone bodies.

Evading the immune system

Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33. (See cancer immunology) Cancer cells tend to employ various strategies that allow them to evade the body’s immune system. This particular hallmark allows tumor cells to hide from, defend against, and hijack stem cells to avoid detection and destruction.

Cancer cells avoid immune destruction by escaping detection. One of the main ways is by expressing the programmed death-1 ligand (PD-L1) on their surface.This protein is usually used to prevent T cells from attacking healthy cells. Tumor cells express PD-L1 in high amounts which prevents T cells from attacking them. Another mechanism that cancer cells use is the downregulation of MHC I. Major histocompatibility complex class I (MHC I) molecules are expressed on cell surfaces with the role of alerting the immune system to the presence of infected cells. Tumor cells escape this aspect of the immune system by suppressing the expression of MHC I through various mechanism such as alteration of transcription factors and epigenetic modifications.

Enabling Characteristics

The updated paper also identified two enabling characteristics. These are labeled as such since their acquisition leads to the development of the hypothesized "hallmarks."

Genome instability

Cancer cells generally have severe chromosomal abnormalities which worsen as the disease progresses. HeLa cells, for example, are extremely prolific and have tetraploidy 12, trisomy 6, 8, and 17, and a modal chromosome number of 82 (rather than the normal diploid number of 46). [37] Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates. (See genome instability)

Inflammation

Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer. Inflammation leads to angiogenesis and more of an immune response. The degradation of extracellular matrix necessary to form new blood vessels increases the odds of metastasis. (See inflammation in cancer)

Criticisms

An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. [38] The only hallmark of malignant disease was its ability to invade and metastasize. [38]

An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. [39] It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading.

See also

Notes and references

  1. 1 2 Hanahan, Douglas; Weinberg, Robert A (7 January 2000). "The Hallmarks of Cancer". Cell. 100 (1): 57–70. doi: 10.1016/S0092-8674(00)81683-9 . PMID   10647931.
  2. 1 2 Hanahan, D.; Weinberg, R. A. (2011). "Hallmarks of Cancer: The Next Generation". Cell. 144 (5): 646–674. doi: 10.1016/j.cell.2011.02.013 . PMID   21376230.
  3. 1 2 Cell 100:59
  4. 1 2 3 4 5 6 Hanahan, D; Weinberg, RA (4 March 2011). "Hallmarks of cancer: the next generation". Cell. 144 (5): 646–74. doi: 10.1016/j.cell.2011.02.013 . PMID   21376230.
  5. 1 2 Evan, GI; Vousden, KH (17 May 2001). "Proliferation, cell cycle and apoptosis in cancer". Nature. 411 (6835): 342–8. Bibcode:2001Natur.411..342E. doi:10.1038/35077213. PMID   11357141. S2CID   4414024.
  6. 1 2 Kunst, Claudia; Haderer, Marika; Heckel, Sebastian; Schlosser, Sophie; Müller, Martina (December 2016). "The p53 family in hepatocellular carcinoma". Translational Cancer Research. 5 (6): 632–638. doi: 10.21037/tcr.2016.11.79 . ISSN   2219-6803.
  7. ↑ McClatchey, AI; Yap, AS (October 2012). "Contact inhibition (of proliferation) redux". Current Opinion in Cell Biology. 24 (5): 685–94. doi:10.1016/j.ceb.2012.06.009. PMID   22835462.
  8. ↑ Elmore, S (June 2007). "Apoptosis: a review of programmed cell death". Toxicologic Pathology. 35 (4): 495–516. doi:10.1080/01926230701320337. PMC   2117903 . PMID   17562483.
  9. ↑ Greenberg, RA (March 2005). "Telomeres, crisis and cancer". Current Molecular Medicine. 5 (2): 213–8. doi:10.2174/1566524053586590. PMID   15974875.
  10. ↑ Cesare, Anthony J.; Reddel, Roger R. (2010). "Alternative lengthening of telomeres: Models, mechanisms and implications". Nature Reviews Genetics. 11 (5): 319–330. doi:10.1038/nrg2763. PMID   20351727. S2CID   19224032.
  11. ↑ Bergers, G; Benjamin, LE (June 2003). "Tumorigenesis and the angiogenic switch". Nature Reviews. Cancer. 3 (6): 401–10. doi:10.1038/nrc1093. PMID   12778130. S2CID   11096398.
  12. ↑ Folkman, Judah (18 November 1971). "Tumor Angiogenesis: Therapeutic Implications". New England Journal of Medicine. 285 (21): 1182–1186. doi:10.1056/NEJM197111182852108. ISSN   0028-4793. PMID   4938153.
  13. ↑ Semenza, Gregg L. (October 2003). "Targeting HIF-1 for cancer therapy". Nature Reviews. Cancer. 3 (10): 721–732. doi:10.1038/nrc1187. ISSN   1474-175X. PMID   13130303.
  14. ↑ Hood, Joshua L.; San, Roman Susana; Wickline, Samuel A. (31 May 2011). "Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis". Cancer Research. 71 (11): 3792–3801. doi:10.1158/0008-5472.CAN-10-4455. ISSN   0008-5472. PMID   21478294.
  15. ↑ van Zijl, F; Krupitza, G; Mikulits, W (2011). "Initial steps of metastasis: cell invasion and endothelial transmigration". Mutation Research. 728 (1–2): 23–34. Bibcode:2011MRRMR.728...23V. doi:10.1016/j.mrrev.2011.05.002. PMC   4028085 . PMID   21605699.
  16. ↑ Celià-Terrassa, Toni; Kang, Yibin (7 February 2024). "How important is EMT for cancer metastasis?". PLOS Biology. 22 (2): e3002487. doi: 10.1371/journal.pbio.3002487 . ISSN   1545-7885. PMC   10849258 . PMID   38324529.
  17. ↑ Liu, Qiu-Luo; Luo, Maochao; Huang, Canhua; Chen, Hai-Ning; Zhou, Zong-Guang (29 April 2021). "Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy". Frontiers in Oncology. 11. doi: 10.3389/fonc.2021.657546 . ISSN   2234-943X. PMC   8117142 . PMID   33996581.
  18. ↑ Sznurkowska, Magdalena K.; Aceto, Nicola (August 2022). "The gate to metastasis: key players in cancer cell intravasation". The FEBS Journal. 289 (15): 4336–4354. doi:10.1111/febs.16046. ISSN   1742-464X. PMC   9546053 . PMID   34077633.
  19. ↑ Egeblad, Mikala; Nakasone, Elizabeth S.; Werb, Zena (June 2010). "Tumors as Organs: Complex Tissues that Interface with the Entire Organism". Developmental Cell. 18 (6): 884–901. doi:10.1016/j.devcel.2010.05.012. PMC   2905377 . PMID   20627072.
  20. 1 2 Kalluri, Raghu (September 2016). "The biology and function of fibroblasts in cancer". Nature Reviews Cancer. 16 (9): 582–598. doi:10.1038/nrc.2016.73. ISSN   1474-175X. PMID   27550820.
  21. ↑ Valastyan, Scott; Weinberg, Robert A. (October 2011). "Tumor Metastasis: Molecular Insights and Evolving Paradigms". Cell. 147 (2): 275–292. doi:10.1016/j.cell.2011.09.024.
  22. ↑ Aceto, Nicola; Bardia, Aditya; Miyamoto, David T.; Donaldson, Maria C.; Wittner, Ben S.; Spencer, Joel A.; Yu, Min; Pely, Adam; Engstrom, Amanda; Zhu, Huili; Brannigan, Brian W.; Kapur, Ravi; Stott, Shannon L.; Shioda, Toshi; Ramaswamy, Sridhar (August 2014). "Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis". Cell. 158 (5): 1110–1122. doi:10.1016/j.cell.2014.07.013. PMC   4149753 . PMID   25171411.
  23. ↑ Massagué, Joan; Obenauf, Anna C. (January 2016). "Metastatic colonization by circulating tumour cells". Nature. 529 (7586): 298–306. Bibcode:2016Natur.529..298M. doi:10.1038/nature17038. ISSN   0028-0836. PMC   5029466 . PMID   26791720.
  24. ↑ Alfarouk, KO; Verduzco, D; Rauch, C; Muddathir, AK; Adil, HH; Elhassan, GO; Ibrahim, ME; David Polo Orozco, J; Cardone, RA; Reshkin, SJ; Harguindey, S (2014). "Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question". Oncoscience. 1 (12): 777–802. doi:10.18632/oncoscience.109. PMC   4303887 . PMID   25621294.
  25. ↑ O. Warburg, K. Posener, E. Negelein: "Ueber den Stoffwechsel der Tumoren" Biochemische Zeitschrift, 152, pp. 319–344, 1924. (German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930.
  26. ↑ "Targeting tumour metabolism". Nature Reviews Drug Discovery. 9 (7): 503–504. 2010. doi:10.1038/nrd3215. ISSN   1474-1776. PMID   20592733. S2CID   7521218.
  27. ↑ Forrest MD. "Why cancer cells have a more hyperpolarised mitochondrial membrane potential and emergent prospects for therapy". bioRxiv   10.1101/025197 .
  28. ↑ Gottlieb E, Armour SM, Harris MH, Thompson CB (2003). "Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis". Cell Death Differ. 10 (6): 709–717. doi: 10.1038/sj.cdd.4401231 . PMID   12761579.
  29. ↑ Vander Heiden, Matthew G., et al. – Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation (2009): This paper discusses how metabolic alterations like the Warburg effect support the growth and survival of cancer cells
  30. ↑ Martinez Marignac, V. L., Smith, S., Toban, N., Bazile, M., & Aloyz, R. (2013). Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming. Oncotarget, 4(12), 2550–2566. https://doi.org/10.18632/oncotarget.1508
  31. ↑ Seyfried, Thomas N., et al. – Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (2012): Seyfried argues that cancer is primarily a metabolic disease caused by mitochondrial dysfunction, leading to abnormal cellular metabolism and growth
  32. ↑ Schwartz, L; Supuran, CT; Alfarouk, KO (2017). "The Warburg Effect and the Hallmarks of Cancer". Anti-Cancer Agents in Medicinal Chemistry. 17 (2): 164–170. doi:10.2174/1871520616666161031143301. PMID   27804847.
  33. ↑ Barañano KW, Hartman AL (2008). "The ketogenic diet: uses in epilepsy and other neurologic illnesses". Curr Treat Options Neurol. 10 (6): 410–9. doi:10.1007/s11940-008-0043-8. PMC   2898565 . PMID   18990309.
  34. ↑ Allen BG, Bhatia SK, Anderson CM, et al. (October 2011). "Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism". Redox Biol. 2C (3): 327–337. doi:10.1016/j.eplepsyres.2011.09.022. PMID   22019313. S2CID   20445641.
  35. ↑ Schwartz, L; Seyfried, T; Alfarouk, KO; Da Veiga Moreira, J; Fais, S (April 2017). "Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH". Seminars in Cancer Biology. 43: 134–138. doi:10.1016/j.semcancer.2017.01.005. PMID   28122260.
  36. ↑ Scheck AC, Abdelwahab MG, Fenton KE, Stafford P (October 2011). "The ketogenic diet for the treatment of glioma: insights from genetic profiling". Epilepsy Res. 100 (3): 327–37. doi:10.1016/j.eplepsyres.2011.09.022. PMID   22019313. S2CID   20445641.
  37. ↑ "HeLa nuclear extract lysate (ab14655)". abcam.
  38. 1 2 Lazebnik Y (April 2010). "What are the hallmarks of cancer?". Nat. Rev. Cancer. 10 (4): 232–3. doi:10.1038/nrc2827. PMID   20355252. S2CID   8862667.
  39. ↑ Sonnenschein C, Soto AM (September 2013). "The aging of the 2000 and 2011 Hallmarks of Cancer reviews: A critique" (PDF). J. Biosci. 38 (3): 651–63. doi:10.1007/s12038-013-9335-6. PMC   3882065 . PMID   23938395.

[1]

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<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<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.

<span class="mw-page-title-main">Catenin</span> Type of protein

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

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.

Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites. Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.

<span class="mw-page-title-main">T-cadherin</span> GPI-anchored signaling protein

T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the cadherin protein family. Unlike typical cadherins that span across the cell membrane with distinct transmembrane and cytoplasmic domains, T-cadherin lacks these features and is instead anchored to the cell's plasma membrane through a GPI anchor.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in humans

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">CYR61</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

<span class="mw-page-title-main">Basal-like carcinoma</span> Breast cancer subtype

The basal-like carcinoma is a recently proposed subtype of breast cancer defined by its gene expression and protein expression profile.

<span class="mw-page-title-main">Epithelial cell adhesion molecule</span> Transmembrane glycoprotein

Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

<span class="mw-page-title-main">SNAI1</span> Protein

Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene. Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.

<span class="mw-page-title-main">Cadherin-1</span> Human protein-coding gene

Cadherin-1 or Epithelial cadherin(E-cadherin), is a protein that in humans is encoded by the CDH1 gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. CDH1 has also been designated as CD324. It is a tumor suppressor gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

A mesenchymal–epithelial transition (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial–mesenchymal transition (EMT) and it has been shown to occur in normal development, induced pluripotent stem cell reprogramming, cancer metastasis and wound healing.

<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.

<span class="mw-page-title-main">Vasculogenic mimicry</span>

Vasculogenic mimicry (VM) is a strategy used by tumors to ensure sufficient blood supply is brought to its cells through establishing new tumor vascularization. This process is similar to tumor angiogenesis; on the other hand vascular mimicry is unique in that this process occurs independent of endothelial cells. Vasculature is instead developed de novo by cancer cells, which under stress conditions such as hypoxia, express similar properties to stem cells, capable of differentiating to mimic the function of endothelial cells and form vasculature-like structures. The ability of tumors to develop and harness nearby vasculature is considered one of the hallmarks of cancer disease development and is thought to be closely linked to tumor invasion and metastasis. Vascular mimicry has been observed predominantly in aggressive and metastatic cancers and has been associated with negative tumor characteristics such as increased metastasis, increased tissue invasion, and overall poor outcomes for patient survival. Vascular mimicry poses a serious problem for current therapeutic strategies due to its ability to function in the presence of Anti-angiogenic therapeutic agents. In fact, such therapeutics have been found to actually drive VM formation in tumors, causing more aggressive and difficult to treat tumors to develop.

A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.

<span class="mw-page-title-main">Invasion (cancer)</span> Direct extension and penetration by cancer cells into neighboring tissues

Invasion is the process by which cancer cells directly extend and penetrate into neighboring tissues in cancer. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to more distant locations. Yet, lymphovascular invasion is generally the first step of metastasis.

Invasion and metastasis are fundamental hallmarks of cancer, representing the ability of the cancer cells to spread from their site of origin to distant tissues and organs. These processes are central to cancer's lethality, accounting for the majority of cancer - related deaths, and marking an important barrier to effective treatment.

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