Hallmarks of Cancer Handbook - Overview, Related Products and Pathways
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Hallmarks of Cancer Handbook Overview, Related Products and Pathways March 2023 (V1.1)
Cancer is one of the leading causes of death worldwide, features of cancer. The book provides an in-depth analysis
affecting millions of people every year. It is a complex and of each of these hallmarks, highlighting the key molecular
multifaceted disease that arises from the uncontrolled pathways and cellular processes involved.
growth of abnormal cells in the body. Despite significant
advancements in cancer research and treatment, the As a platform for high-quality research antibodies, proteins,
fight against this disease is far from over. There is a need and kits, antibodies-online has a deep understanding of the
for continued research into the mechanisms of cancer importance of reliable and accurate research materials for
development and progression, as well as the development of cancer research. This book also provides a comprehensive
new and effective treatments. guide to the various research materials available for cancer
research, including antibodies, proteins, and assay kits. It
This book aims to give an introduction into cancer research, offers insights into the selection and use of these materials,
focusing on the publication “Hallmarks of Cancer” by Douglas highlighting the critical role they play in cancer research.
Hanahan and Robert A. Weinberg, which identifies key
Contents
1. Hallmarks of Cancer
Sustaining Proliferative Signaling................................................................................................................................ 4
Evading Growth Suppressors....................................................................................................................................... 4
Resisting Cell Death..................................................................................................................................................... 5
Limitless Replicative Potential.................................................................................................................................... 5
Senescent Cells............................................................................................................................................................ 5
Deregulating Cellular Metabolism............................................................................................................................... 6
Avoiding Immune Destruction..................................................................................................................................... 6
Sustained Angiogenesis.............................................................................................................................................. 6
Activating Invasion & Metastasis................................................................................................................................ 6
Unlocking Phenotypic Plasticity.................................................................................................................................. 7
2. Additional Resources
Cancer Immune Checkpoints...................................................................................................................................... 9
Cancer Immunity Cycle................................................................................................................................................ 10
CAR-T Immunotherapy Research................................................................................................................................ 11
Popular CAR-T Immunotherapy Targets..................................................................................................................... 12
3. Related Pathways
Apoptosis Pathway....................................................................................................................................................... 14
Cell Division Cycle Pathway......................................................................................................................................... 15
DNA Damage Repair Pathway..................................................................................................................................... 16
Epigenetics.................................................................................................................................................................... 17
Extracellular Matrix....................................................................................................................................................... 19
Hedgehog Signaling Pathway...................................................................................................................................... 20
Inflammasome Pathway.............................................................................................................................................. 21
Notch Signaling Pathway............................................................................................................................................. 22
RTK Signaling Pathway................................................................................................................................................ 23
TCR Signaling................................................................................................................................................................ 24
Warburg Effect.............................................................................................................................................................. 25
WNT Signaling Pathway............................................................................................................................................... 26
©2023 2
1. Hallmarks of
Cancer
4
Sustaining Proliferative Signaling
4
Evading Growth Suppressors
5
Resisting Cell Death
5
Limitless Replicative Potential
5
Senescent Cells
6
Deregulating Cellular Metabolism
6
Avoiding Immune Destruction
6
Sustained Angiogenesis
6
Activating Invasion & Metastasis
7
Unlocking Phenotypic Plasticity
Hallmarks of Cancer
Sustained
Proliferative
Unlocking Evading
Signaling
Phenotypic Growth
Plasticity Suppressors
Deregulating Epigenetic
Cellular Reprogramming
Resisting Avoiding
Cell Immune
Death Destruction
Genome Limitless
Instability Replicative
& Mutation Potential
Senescent Tumor
Cells Promoting
Inflammation
Sustained
Polymorphic
Angiogenesis Activating Microbiomes
Invasion
& Metastasis
In 2000, Douglas Hanahan and Robert Weinberg published of mutations in genes that encode proteins involved in these
the paper ‘The hallmarks of cancer’, conceptualizing six signaling pathways, leading to the activation of downstream
core rules which orchestrate the multistep transformation of signaling molecules that promote cell growth.
normal cells into malignant cells. More than 20 years later, in
the third update ‘Hallmarks of cancer: new dimensions’, these Jump to:
six original hallmarks have expanded to 14. These hallmarks RTK Signaling Pathway
outline a set of criteria that explain how normal cells can
develop into malignant tumors by identifying specific
characteristics and describing how they interact with one Evading Growth Suppressors
another. These characteristics include sustained proliferative
signaling, evasion of growth suppressors, resistance to A highly complementary hallmark capability for sustaining
cell death, limitless replicative potential, angiogenesis, proliferative signaling in cancer cells is the ability to evade
and genomic instability. Together, these hallmarks allow growth suppression. Growth suppressor genes normally
cancer cells to evade the normal controls that regulate cell function to inhibit cell growth and division. Several tumor
growth and division, enabling them to continue to divide and suppressive protein-coding genes that operate in diverse
proliferate, forming a tumor that can invade nearby tissues ways to inhibit cellular growth and proliferation had been
and spread to other parts of the body. Below you may find a discovered. Prominent examples are the retinoblastoma
brief summary of the respective hallmarks as well as related protein (RB) or the human tumor suppressor p53. The
resources (e.g. pathway illustrations) and research tools (i.e. transcription factor regulates the expression of genes
antibodies, ELISA kits, recombinant proteins). involved in cell cycle control, induction of apoptosis or DNA
repair after DNA damage. In cancer cells, these genes are
often inactivated, either through mutations that disable their
Sustaining Proliferative Signaling function or by mechanisms that prevent them from being
expressed. This allows cancer cells to avoid the normal
The most fundamental trait of cancer cells involves their constraints on cell growth and division, enabling them to
ability to sustain chronic proliferation. This refers to the ability continue to proliferate unchecked.
of cancer cells to activate signaling pathways that promote
cell growth and division. Normally, these pathways are tightly Jump to:
regulated, but in cancer cells, they are constantly activated, Cell Division Cycle Pathway
allowing the cells to continue to divide and proliferate even in DNA Damage Repair
the absence of normal growth signals. This can be the result
1. Hallmarks of Cancer ©2023 4
Resisting Cell Death Senescent Cells
In addition to evading growth suppressors, cancer cells also Cellular senescence is a form of cell growth arrest that is
have a high degree of resistance to cell death. Normally, cells typically irreversible, and it is thought to have evolved as a
undergo programmed cell death, or apoptosis, when they protective mechanism to maintain tissue homeostasis. It is
become damaged or no longer needed. The cancer cells may considered as a complementary mechanism to programmed
alter the mechanisms that detect the damage or irregularities, cell death, which serves to deactivate and eventually
preventing proper signaling and apoptosis activation. Cancer remove cells that are diseased, dysfunctional, or no longer
cells may also introduce defects in the downstream signaling needed. Senescence can be induced in cells by a variety
itself, or the proteins involved, which would also prevent of conditions, including microenvironmental stresses like
proper apoptosis. This can be the result of mutations in genes nutrient deprivation and DNA damage, as well as damage
that regulate the apoptotic pathway, or it can be due to the to organelles and cellular infrastructure, and imbalances in
activation of signaling pathways that promote cell survival. cellular signaling networks.
Jump to: Cellular senescence has long been considered a protective
Apoptosis Pathway mechanism against tumors, whereby cancerous cells
are induced to undergo senescence. Majority of triggers
mentioned above are associated with malignancy—
Limitless Replicative Potential particularly DNA damage as a consequence of aberrant
hyperproliferation, also know as oncogene-induced
The potential to replicate without limitation is another key senescence due to hyperactivated signaling. However,
aspect in tumor development, which is also recognized as new publications question this linear relationship. In
hallmark of cancer. In contrast to human body cells, cancer certain contexts, senescent cells variously stimulate tumor
cells can overcome the ‘Hayflick Limit’ and divide indefinitely, development and malignant progression. The principal
without undergoing the normal process of cellular aging. mechanism by which senescent cells promote tumor
Normally cells entering the state of senescence, or cell phenotypes is thought to be via senescence-associated
death stop replication. This is mainly due to the DNA at the secretory phenotypes (SASP).
end of chromosomes, known as telomeres. Telomeric DNA
shortens with every cell division, until it becomes so short it Jump to:
activates senescence, so the cell stops dividing. Cancer cells Apoptosis Pathway
bypass this barrier by manipulating the enzyme telomerase DNA Damage Repair Pathway
to increase the length of telomeres. Thus, they can divide
indefinitely, without initiating senescence.
Senescence-Associated Secretory
Jump to: Phenotype (SASP)
Cell Division Cycle Pathway
Hedgehog Signaling Pathway Multiple types of stimuli can provoke cellular
senescence and SASP. When irreversible cell-
cycle arrest is triggered by severe DNA damage
The Hayflick Limit (i.e. dysfunctional telomeres or oncogenic
stress), the SASP occurs in senescent cells. The
In mammalian cells the Hayflick Limit defines the acquisition of a SASP turns senescent fibroblasts
amount of maximal cell divisions. After 60–70 into proinflammatory cells that have the ability to
doublings the cells reach a stage of senescence and promote tumor progression. Senescent cells secrete
multiplication is stopped. This limit can be overcome interleukins, inflammatory cytokines, and growth
by disabling their RB and P53 tumor suppressor factors that can affect surrounding cells. The most
proteins, which allows them to continue doubling until prominent cytokine of the SASP is interleukin-6 (IL-6),
they reach a crisis, with apoptosis or rare occuring a pleiotropic proinflammatory cytokine. IL-6 has been
emergence of an immortalized cell that can double shown to be associated with DNA damage– and
without limit. Most tumor cells are immortalized. oncogenic stress–induced senescence of mouse
and human keratinocytes, melanocytes, monocytes,
Telomere decreases in size during each cell cycle. fibroblasts, and epithelial cells. Further, IL-6 secretion
About 85% of cancers upregulate telomerase to appears to be directly controlled by persistent DNA-
extend their telomeres and the remaining 15% use damage signaling (ATM and CHK2), independent of
alternative lengthening of telomeres. the p53. Through IL-6 expression, senescent cells can
directly affect neighboring cells.
RB P53
IL-6 ATM CHK2
1. Hallmarks of Cancer ©2023 5
Deregulating Cellular Metabolism
For unhindered growth, tumors not only benefit from
deregulated control of cell proliferation but also
corresponding adjustments of energy metabolism to fuel Tissue Inhibitors of Metalloproteinases
cell growth and division. They have the capability to modify (TIMPs)
or reprogram cellular metabolism to efficiently support
neoplastic proliferation. Under aerobic conditions, normal The TIMP family consist of members (TIMP
cells process glucose, first to pyruvate via glycolysis in the 1-4). They are able to are able to inhibit matrix
cytosol and secondly, to carbon dioxide in the mitochondria; metalloproteinases (MMPs) by forming tight-binding,
under anaerobic conditions, glycolysis is favored, and noncovalent associations with the active site of
relatively little pyruvate is dispatched to the oxygen- the MMPs. MMPs play a big role in the proliferation
consuming mitochondria. Otto Warburg was the first to of tumors, they facilitate tumor cell invasion and
observe an anomalous characteristic of cancer cell energy metastasis by at least three distinct mechanisms.
metabolism. First, proteinase action removes physical barriers to
invasion through degradation of ECM macromolecules
Jump to: such as collagens, laminins, and proteoglycans.
Warburg Effect Second, MMPs have the ability to modulate cell
adhesion, crucial for cell movement through the ECM.
The ratio of MMP-2 to TIMP-2 significantly impacts
Avoiding Immune Destruction variation in the adhesive phenotype of tumor cells.
Finally, MMPs especially MMP-2, MMP-9 and MMP-14
are prone to metastasis, they support the degradation
Some cancer cells adapt mechanisms to evade both immune
of basement membranes and the establishment of
surveillance and attack by the host’s immune system. One
tumorigenic blood vessels. Laminin-alpha-5 induces
way cells do this is by hijacking normal mechanisms of
MMP-9 expression and thus supports Epithelial-
immune checkpoint control. Immune checkpoints refer to
Mesenchymal Transition (EMT).
the built-in control mechanisms of the immune system that
maintain self-tolerance and help to avoid collateral damage
during a physiological immune response. Tumor-specific T MMP-2 MMP-9 MMP-12 MMP-13 TIMP-2
cells must discriminate between destruction of the tumor
Laminin-
cell and survival of the target cell. What is important for
alpha-5
discrimination are proteins on both the T-cell and the target
cell. Tumor cells express molecules to induce apoptosis or
to inhibit T lymphocytes, for example, PD-L1 on the surface
of tumor cells leads to suppression of T lymphocytes. FasL
Activating Invasion & Metastasis
on the other hand may induce apoptosis of T lymphocytes.
Some cancer cells also try to gain resistance against possible
The ability to invade neighboring tissues is what dictates
cytotoxic CD8+ T cell which are a fundamental element of
whether the tumor is benign or malignant, and it renders
anti-tumor immunity. They lower their MHC I expression and
cancer a mortal threat. Metastasis enables their
avoid being detected by the cytotoxic T cells. Disruption of the
dissemination around the body complicates treatment by
apoptotic signal pathway molecules also leads to successful
a large margin. The cancer cells must undergo a multitude
immune evasion by the tumor. Caspase 8, Bcl-2 or IAP are key
of changes in order for them to acquire the ability to
targets, among others.
metastasize. The metastatic cascade represents a multi-step
process which includes local tumor cell invasion, invasion of
Jump to:
blood vessels followed by the exit of carcinoma cells from the
Cancer Immune Checkpoints
circulation and colonization in the new tissue. At the earliest
stage of successful cancer cell dissemination, the primary
cancer adapts the secondary site of tumor colonization
Sustained Angiogenesis involving the tumor-stroma crosstalk.
An expanding tumor has an increased need for nutrients
to sustain his growth and spread. The tumor requires new
blood vessels to deliver adequate oxygen to the cancer cells.
To do this, the cancer cells acquire the ability to undergo
angiogenesis, the process of forming new blood vessels.
Cancer cells orchestrates the production of new vasculature
by releasing signaling molecules that activate the ‘angiogenic
switch’. By exploiting the switch, non-cancerous cells that are
present in the tumor are stimulated to form blood vessels.
1. Hallmarks of Cancer ©2023 6
Unlocking Phenotypic Plasticity
Epithelial- Mesenchymal Transition
Relative to the huge amount of development and
differentiation that occurs during organogenesis, mammalian
The ‘Epithelial-Mesenchymal Transition’ (EMT), a
cells are typically restricted in the extent to which they
process involved in various steps of embryonic
can differentiate. This restriction allows cells to remain
morphogenesis and wound healing, is being used by
organized and functional within their respective tissue. In
carcinoma cells to acquire multiple attributes that
cancer, however, cells undergo molecular and phenotypic
enable invasion and metastasis. This multifaceted
changes that allow them to adopt different identities along
EMT program can be activated transiently or stably,
a phenotypic spectrum referred to as cellular plasticity.
and to differing degrees, by carcinoma cells during
This includes dedifferentiation from mature to progenitor
the course of invasion and metastasis. The transition
states, blocked differentiation from progenitor cell states,
is an example for the hallmark enabling characteristic
and transdifferentiation into different cell lineages. The
‘phenotypic plasticity’. Transcriptional factors,
EMT and mesenchymal-to-epithelial (MET) transitions are
including Snail, Slug, Twist, and Zeb1/2, orchestrate
well-characterized examples of developmental regulatory
the EMT and related migratory processes during
programs that resemble transdifferentiation. Changes in
embryogenesis. They are also expressed in various
cellular phenotype are important to cancer progression
combinations in a number of malignant tumor types
because these changes can facilitate tumor initiation and
and are involved in carcinoma formation and for
metastasis, immune invasion, chemoresistance and many
programming invasion.
other aspects of tumor progression.
Snail Slug Twist Zeb1/2 SETD1B
Click here to see an online version of this article
References
• Hanahan, Weinberg: “The hallmarks of cancer.” in: Cell, Vol. 100, Issue 1, pp. 57-70, (2000).
• Hanahan, Weinberg: “Hallmarks of cancer: the next generation.” in: Cell, Vol. 144, Issue 5, pp. 646-74, (2011).
• Hanahan: “Hallmarks of Cancer: New Dimensions.” in: Cancer discovery, Vol. 12, Issue 1, pp. 31-46, (2022).
• Wong, Chim: “DNA methylation of tumor suppressor protein-coding and non-coding genes in multiple myeloma.” in: Epigenomics, Vol. 7, Issue 6, pp. 985-1001,
(2016).
• Hackermüller, Reiche, Otto, Hösler, Blumert, Brocke-Heidrich, Böhlig, Nitsche, Kasack, Ahnert, Krupp, Engeland, Stadler, Horn: “Cell cycle, oncogenic and tumor
suppressor pathways regulate numerous long and macro non-protein-coding RNAs.” in: Genome biology, Vol. 15, Issue 3, pp. R48, (2015).
• Zhang, Zou: “Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks.” in: Cell & bioscience, Vol. 10, pp. 30, (2020).
• Saman, Raza, Uddin, Rasul: “Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches.” in: Cancers, Vol. 12, Issue 5, (2020).
• Kleiner, Stetler-Stevenson: “Matrix metalloproteinases and metastasis.” in: Cancer chemotherapy and pharmacology, Vol. 43 Suppl, pp. S42-51, (1999).
• Lythgoe, Mullish, Frampton, Krell: “Polymorphic microbes: a new emerging hallmark of cancer.” in: Trends in microbiology, Vol. 30, Issue 12, pp. 1131-1134,
(2022).
• van Zijl, Krupitza, Mikulits: “Initial steps of metastasis: cell invasion and endothelial transmigration.” in: Mutation research, Vol. 728, Issue 1-2, pp. 23-34, (2011).
• Qin, Jiang, Lu, Nice, Huang, Zhang, He: “Emerging role of tumor cell plasticity in modifying therapeutic response.” in: Signal transduction and targeted therapy,
Vol. 5, Issue 1, pp. 228, (2021).
• Kadosh, Snir-Alkalay, Venkatachalam, May, Lasry, Elyada, Zinger, Shaham, Vaalani, Mernberger, Stiewe, Pikarsky, Oren, Ben-Neriah: “The gut microbiome
switches mutant p53 from tumour-suppressive to oncogenic.” in: Nature, Vol. 586, Issue 7827, pp. 133-138, (2021).
• Dzutsev, Badger, Perez-Chanona, Roy, Salcedo, Smith, Trinchieri: “Microbes and Cancer.” in: Annual review of immunology, Vol. 35, pp. 199-228, (2018).
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• Mirzaei, Hamblin: “Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect.” in: Molecular therapy oncolytics, Vol. 19, pp. 218-
239, (2020).
• Greten, Grivennikov: “Inflammation and Cancer: Triggers, Mechanisms, and Consequences.” in: Immunity, Vol. 51, Issue 1, pp. 27-41, (2019).
• Faget, Ren, Stewart: “Unmasking senescence: context-dependent effects of SASP in cancer.” in: Nature reviews. Cancer, Vol. 19, Issue 8, pp. 439-453, (2019) .
• Kowald, Passos, Kirkwood: “On the evolution of cellular senescence.” in: Aging cell, Vol. 19, Issue 12, pp. e13270, (2021).
• Negrini, Gorgoulis, Halazonetis: “Genomic instability--an evolving hallmark of cancer.” in: Nature reviews. Molecular cell biology, Vol. 11, Issue 3, pp. 220-8,
(2010).
• Skrypek, Goossens, De Smedt, Vandamme, Berx: “Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity.” in: Trends in
genetics : TIG, Vol. 33, Issue 12, pp. 943-959, (2018).
• Anderson, Simon: “The tumor microenvironment.” in: Current biology : CB, Vol. 30, Issue 16, pp. R921-R925, (2021).
1. Hallmarks of Cancer ©2023 7
2. Additional
Resources
9
Cancer Immune Checkpoints
10
Cancer Immunity Cycle
11
CAR-T Immunotherapy Research
12
Popular CAR-T Immunotherapy TargetsCancer Immune Checkpoints
Immune checkpoints are receptors on the membrane application of immune-checkpoint inhibitors has dramatically
of T-lymphocytes that can regulate their immune improved the treatments, outcomes and therapeutic concepts
response. They are refinely tuned and alternate between in multiple tumor settings. Of the immune checkpoint proteins
stimulation and inhibition1. The immuno checkpoints identified to date, CTLA-4 is a critical regulator of T-cell
pathway is crucial to promote self-tolerance and prevent responses. CTLA-4 is structurally similar to the co-stimulating
autoimmunity and related diseases. receptor CD28, with both receptors also binding to CD80 and
CD86 (also known as B7-1 and B7-2). Binding to CD80 or
T-cell receptors are in focus of medical research, however, CD86 leads to a competition between an inhibitory signal (by
global immunosuppression greatly increases the risk of CTLA-4) and a co-stimulating signal (by CD28). In 2018 the
acquiring life-threatening infections and is associated research on monoclonal antibodies blocking the inhibitory
with organ toxicity when used long-term. Thus, alternative molecule CTLA-4 and or the PD-1/PD-L1 axis by James P.
approaches that inhibit only the unwanted immune Allison & Tasuku Honjo, was awarded with The Nobel Prize in
responses and preserve general immunity are highly Physiology or Medicine.
desirable. The tumor necrosis factor (TNF) receptor
superfamily represents the largest part of receptors with Click here to see an online version of this article
CD27, CD40, OX40, GITR and CD137. Two additional
stimulatory checkpoint molecules belong to the B7-CD28
superfamily: CD28 itself and ICOS.
Antigen-presenting Cell T Cell
4-1BBL 4-1BB CD137
Co-Stimulation and Inhibition with BTLA Adenosine ADORA2A
and HVEM CD80/86
BLAST-1
B7-1/2
ACVR2B
CTLA4 CD279 CD28
B7-H3 TLT2
The HVEM/ LIGHT/BTLA/CD160 costimulatory/ B7-H4 B7-H4R
coinhibitory pathway has emerged as a potential target B7-H6 NKp30
for the development of immune therapeutic interventions. CD40 CD40L
The interaction between BTLA, short for B and T TNFSF7 CD70 CD27 TNFRSF7
Lymphocyte Attenuator, an inhibitory receptor whose CD274 B7-H1 PD-L1/L2 PD-1
extracellular domain belongs to the immunoglobulin CD275 ICOSL B7RP1 CD278 ICOS
superfamily, and herpesvirus-entry mediator (HVEM),
GAL-9 TIM-3
KIR L
a co-stimulatory tumour-necrosis factor receptor, is LAG-3
unique in that it is the only receptor–ligand interaction MHC Class I TCR Complex
that directly links these two families of receptors. Signal
Recent studies show that engagement of HVEM with MHC Class II TCR Complex
its endogenous ligand (LIGHT) from the tumour- KIR S
necrosis factor family induces a powerful immune
GITRL GITR
BTLA CD272
response. LIGHT stimulates the proliferation of T cells, HVEM
HVEM
LIGHT
and triggers apoptosis of various tumor cells, whereas Nectin-2
DNAM-1
HVEM interactions with BTLA negatively regulate T-cell
Nectin-2 TIGIT
PVR
responses.
PVR TACTILE
OX-2 OX-2R
OX40L OX40
Importance of Checkpoint Inhibitors for VISTA VSIG-3
Cancer Immunotherapy
Cytokines
TGFß, IL-1, IL-6, IL-10, IL-12, IL-18
Inhibitory checkpoint molecules are promising targets
for cancer immunotherapy. The discovery and clinical
References
• Hughes, Bundred: “Breast macrocysts.” in: World journal of surgery, Vol. 13, Issue 6, pp. 711-4, (1990).
• James P. Allison and Tasuku Honjo : “for their discovery of cancer therapy by inhibition of negative immune regulation”. The Nobel Assembly at Karolinska
Institutet (2018). [Press Release]
• Murphy, Nelson, Sedý: “Balancing co-stimulation and inhibition with BTLA and HVEM.” in: Nature reviews. Immunology, Vol. 6, Issue 9, pp. 671-81, (2006).
• del Rio, Fernandez-Renedo, Chaloin, Scheu, Pfeffer, Shintani, Perez-Simon, Schneider, Rodriguez-Barbosa: “Immunotherapeutic targeting of LIGHT/LTβR/HVEM
pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.” in: mAbs, Vol. 8, Issue 3, pp. 478-90, (2016).
• Rowshanravan, Halliday, Sansom: “CTLA-4: a moving target in immunotherapy.” in: Blood, Vol. 131, Issue 1, pp. 58-67, (2018).
2. Additional Resources | Cancer Immune Checkpoints ©2023 9Cancer Immunity Cycle
The cancer immunity cycle provides a framework for immune response is determined, with the ratio of T effector
understanding the complex interactions between cancer cells cells and T regulatory cells being decisive for the final
and the immune system. For an anticancer immune response outcome.
to lead to effective killing of cancer cells, all stages of the
cycle must be passed through. By understanding the different Finally, the activated effector T cells migrate to the tumor
stages of the cycle, researchers can develop new therapies microenvironment (stage 4) in order to infiltrate (stage 5).
that target specific stages and improve the ability of the They specifically recognize and bind to cancer cells through
immune system to recognize and eliminate cancer cells. the interaction between its T cell receptor (TCR) and its
cognate antigen bound to MHCI (stage 6). Once bound to
In the first stage neoantigens created by oncogenesis are cancer cells, T cells release toxic molecules that kill the
released and captured by dendritic cells for processing. cancer cells (stage 7), which leads to lysis and re-release of
For a successful anticancer T cell response, they must be new neoantigens. The cycle repeats.
accompanied by signals that specify immunity to avoid
peripheral tolerance to the tumor antigens. Important signals In cancer patients, the Cancer-Immunity Cycle does not
like proinflammatory cytokines and factors released by dying perform optimally. Tumor antigens may not be detected,
tumor cells or by the gut microbiota. dendritic cells and T cells may treat antigens as self rather
than foreign thereby creating T regulatory cell responses
Next, dendritic cells present the captured antigens on MHCI rather than effector responses, T cells may not properly home
and MHCII molecules to T cells (stage 2). This presentation to tumors, may be inhibited from infiltrating the tumor, or
of cancer cell antigens is essential for the activation of the (most importantly) factors in the tumor microenvironment
immune response. The presentation results in the priming might suppress those effector cells that are produced.
and activation of effector T cell responses against the
cancer-specific antigens (stage 3). Priming prepares them to Click here to see an online version of this article
recognize and attack cancer cells. At this stage, the type of
Priming and Ac�va�on
Migra�on
CD28/B7.1 HVEM 3 4 of T Cells
CD137/CD137L IL-2
OX40/OX40L IL-12 CX3CL1
CD27/CD70 GITR CXCL9
CXCL10
CTLA4/B7.1 CCL5
PD-L1/PD-1
PD-L1/B7.1
prostaglandins
LymphNode
Infiltra�on of T Cell
Cancer An�gen 5 into Tumors
Presenta�on
2 BloodVessel LFA1/ICAM1
TNF-α Selectins
IL-1 VEGF
IFN-α Endothelin B receptor
CD40L/CD40
CDN
ATP
HMGB1 Tumor
TLR
IL-10
IL-4
IL-13
Cancer Cell
6 Recogni�on
Release of Cancer
1
T cell receptor
Cell An�gens Reduced pMHC
Immunogenic cell death on cancer cells
Tolerogenic cell death
7 Lysis of Cancer Cells
IFN-γ
T cell granule content
PD-L1/PD-1 LAG-3
PD-L1/B7.1 Arginase
IDO MICA/MICB
TGF-β B7-H4
BTLA TIM-3/phospholipds
VISTA
Fig. 1: Cancer immunity cycle
References
• Kaufman, Atkins, Subedi, Wu, Chambers, Joseph Mattingly, Campbell, Allen, Ferris, Schilsky, Danielson, Lichtenfeld, House, Selig: “The promise of Immuno-
oncology: implications for defining the value of cancer treatment.” in: Journal for immunotherapy of cancer, Vol. 7, Issue 1, pp. 129, (2020).
• Esfahani, Roudaia, Buhlaiga, Del Rincon, Papneja, Miller: “A review of cancer immunotherapy: from the past, to the present, to the future.” in: Current oncology
(Toronto, Ont.), Vol. 27, Issue Suppl 2, pp. S87-S97, (2021).
• Chen, Mellman: “Oncology meets immunology: the cancer-immunity cycle.” in: Immunity, Vol. 39, Issue 1, pp. 1-10, (2013).
2. Additional Resources | Cancer Immunity Cycle ©2023 10CAR-T Immunotherapy Research
As revolutionary immuno-oncology changes to cancer a bridge to connect genetically modified T cells to the surface
treatment, cell therapies have attracted widespread attention antigens of tumor cells based on targeted ligands. Clinical
with their high clinical remission rate in hematological trials have demonstrated compelling overall response and
cancers. Since 2018, cell therapies have accounted for more survival rates in individuals with B-cell malignancies.
remissions than cancer vaccines, with chimeric antigen
receptor T (CAR-T) therapies leading the global cell therapy
development race. With rapid development in the past ten The most popular CAR-T Targets
years, CAR-T immunotherapy has become a hot area in which
commercial organizations compete fiercely and universities According to data from the U.S. Patent and Trademark Office
ans industry collaborate intensively. (USPTO), the number of CAR-T related patents filed showed
a sharp increase during the last decade. In this context, the
Chimeric antigen receptor (CAR) T-cell therapy represents USA and China are leading the way with the largest increase
a major advancement in personalized cancer treatment. in patent documents, followed by the European countries. A
In this strategy, a patient’s own T cells are genetically look at the most common targets in CAR-T patent documents
engineered to express a synthetic receptor that binds a tumor reveals an interesting and clearly structured picture. CD19
antigen. CAR-T cells are then expanded for clinical use and is by far the most worked target, followed by BCMA, CD20,
infused back into the patient’s body to attack and destroy Mesothelin, PD-1/PD-L1.
chemotherapy-resistant cancer. CAR-T cell therapy leverages
the power of the patient’s own immune system by serving as Click here to see an online version of this article
CD19
BCMA
CD20
Mesothelin
PD-1/PD-L1
HER-2
CD22
EGFR
MUC1
HLA
EGFRvIII
CD33
CD123
CD30
ROR1
GPC3 T-Cell CAR CAR-T Cell
CEA
PSMA
CD38
GD2
02 0 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
Fig. 1: Top-20 targets in CAR-T patents
References
• Lyu, Feng, Chen, Hu: “The global chimeric antigen receptor T (CAR-T) cell therapy patent landscape.” in: Nature biotechnology, Vol. 38, Issue 12, pp. 1387-1394,
(2021).
• Feins, Kong, Williams, Milone, Fraietta: “An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer.” in: American journal of
hematology, Vol. 94, Issue S1, pp. S3-S9, (2020).
• Lamprecht, Dansereau: “CAR T-Cell Therapy: Update on the State of the Science.” in: Clinical journal of oncology nursing, Vol. 23, Issue 2, pp. 6-12, (2020).
2. Additional Resources | CAR-T Immunotherapy Research ©2023 11Popular CAR-T Immunotherapy Targets
Product Reactivity Clonality Clone Application Cat. No. Validations
Coat, ELISA, FACS,
CD19 antibody Human Monoclonal CD19-3116 ABIN6941101 (5)
IHC, StM
Coat, ELISA, IHC,
BCMA antibody Human Monoclonal BCMA-2366 ABIN6940533 (4)
StM
Coat, ELISA, FACS,
CD20 antibody Human Monoclonal MS4A1-3409 ABIN6941105 (6)
IF, IHC, StM, WB
(2)
Mesothelin antibody Human Monoclonal MB-G10 IHC, WB ABIN233752
(3)
ELISA, FACS, ICC,
PD-1 antibody Human Monoclonal 3E12A10 ABIN5611149 (4)
IHC, Neut, WB
Human, Mouse, ELISA, ICC, IF, IHC,
ErbB2/Her2 antibody Polyclonal ABIN6256630 (12)
Rat WB
ICC, FACS, ELISA, (2)
CD22 antibody Human Monoclonal 1A3A11 ABIN1724887
WB (5)
(3)
EGFR antibody Human Polyclonal IP, ELISA, WB ABIN98862
(2)
Human, Mouse, Coat, ELISA, FACS,
MUC1 antibody Monoclonal ABIN6940096 (6)
Rat IF, IHC, StM, WB
ELISA, FACS, ICC, (11)
HLAG antibody Human Monoclonal MEM-G-9 ABIN94373
IHC (fro), IP (4)
IF (p), IHC (p), (9)
EGFRviii antibody Human Polyclonal ABIN742035
WB (5)
CD33 antibody Human Polyclonal IF, IHC, WB ABIN3022816 (6)
Coat, ELISA, IHC, ISt,
IL3RA antibody Human Monoclonal IL3RA-2947R ABIN6939784 (3)
StM
(1)
TNFRSF8 antibody Human Monoclonal 3B10 FACS, ELISA, WB ABIN969019
(4)
(1)
ROR1 antibody Human Monoclonal 2H6 ICC, ELISA, WB ABIN969385
(2)
ICC, FACS, IHC, (2)
Glypican 3 Human, Mouse Monoclonal 9C2 ABIN969523
ELISA, WB (7)
CEA antibody Human Monoclonal Arcitumomab BI, FACS, IHC (p) ABIN5668278 (2)
Human, Mouse, (9)
PSMA antibody Monoclonal GCP-04 ICC, IHC (p), WB ABIN1302364
Pig, Rat (8)
CD38 antibody Human Monoclonal 5C5C3 ELISA, IHC, WB ABIN5542494 (5)
GM2A antibody Human Polyclonal ELISA, IHC, IP, WB ABIN7153574 (4)
2. Additional Resources | Popular CAR-T Immunotherapy Targets ©2023 123. Related
Pathways
14
Apoptosis Pathway
15
Cell Division Cycle Pathway
16
DNA Damage Repair Pathway
17
Epigenetics
19
Extracellular Matrix
20
Hedgehog Signaling Pathway
21
Inflammasome Pathway
22
Notch Signaling Pathway
23
RTK Signaling Pathway
24
TCR Signaling
25
Warburg Effect
26
WNT Signaling PathwayApoptosis Pathway
Programmed cell death or apoptosis is an important procaspases (e.g. procaspases 8, 9, 10) are aggregated
physiological process in multicellular organisms. The with the help of adaptor proteins, thus facilitating mutual
equilibrium between cell growth and division and the activation due to low protease activity or conformational
rate at which cells undergo cell death allows for dynamic changes of the procaspases. The activated caspases are then
adjustment of the cell number depending on internal or free to activate effector caspases (e.g. caspases 3, 6, and 7)
external parameters. For example, during the development and promote apoptosis. Their effect is further regulated by
of the vertebrate nervous system about half of the cells Bcl-2 family proteins (e.g. Bcl-2, Bcl-xL) and IAPs (inhibitors of
undergo apoptosis shortly after they have been formed. In apoptosis, e.g. BIRC1, XIAP).
an adult organism, this equilibrium is essential to maintain
for example the size and function of organs and tissues. Apoptotic processes follow several pathways. Extrinsic death
Dysregulation of this equilibrium oftentimes leads to cancer. receptor pathways are induced through ligands that bind to
Unlike necrosis which causes a potentially damaging a family of death receptor proteins (e.g. the FAS and TRAIL
inflammatory response after affected cells burst, apoptosis receptors) containing a cytoplasmic death domain. The
unfolds in a very organized way: the cell shrinks and intrinsic pathway is engaged in response to DNA damage or
condenses while the internal structures are disassembled mitochondrial stress and is particularly relevant in cancer.
and the DNA is fragmented. The dying cell is then rapidly Besides these canonical apoptotic pathways there are also
phagocytosed by neighboring cells or macrophages. caspase independent pathways, triggered e.g. by granzyme B
and A. These caspase independent pathways are thought to
At the core of the apoptotic process are caspases, a family have evolved in response to viruses that inhibit caspases.
of cysteine proteases. They are produced as pro-caspases
which are rendered active subsequently to cleavage by other Click here to see the online version of this article and
caspases. This caspase cascade is triggered when initiator the related antibodies, proteins, and ELISA kits
Extrinsic Intrinsic
Pathway Pathway
Death receptors: Chemicals, radiation &
TNFRI, CD95/Fas, growth factor withdrawal
TRAILR
BCL-2
Pro BCL-xL BH3 only
TRADD FADD proteins
caspase 8 MCL-1
TRAF2 RIP
cIAPs Ub p53
Ub Ub
Ub Ub BAX
Ub BID
BAK
TRAF2 TRADD FADD
Pro Active
cIAPs RIP caspase 8 caspase 8 C C C
IAP tBID
antagonists
Caspase C
3/7 Caspase 9 Caspase 9
Apaf-1
Ub Non-degradative Ub
Ub
Ub Degradative Ub Ub
XIAP SMAC
C Cytochrome C
IAP
cIAPs
antagonists
3. Related Pathways | Apoptosis Pathway ©2023 14Cell Division Cycle Pathway
All organisms (single and multi-cellular) rely upon reiteration between the G1 and S phase. A second opportunity for arrest
of growth and division of existing cells under favorable is provided between G2 and M phases. Once DNA replication
conditions. During each round of this process, the cell cycles has been initiated, it must be finished. Therefore, the major
through an ordered series of events in which its genetic checkpoint in the cell cycle is the restriction (R) point between
information is duplicated and then divided among two G1 and S phases, prior to DNA duplication, at which the cycle
daughter cells. These events are tightly regulated and certain progresses depending on mitogenic or inhibitory factors such
checkpoints must be passed in order for the cell cycle to as DNA damage and signals from various signaling pathways.
be completed. The loss of control of these processes is a
hallmark of cancer. Progression from one phase to another is controlled by cyclin
dependent kinases (CDK) and their activators, cyclins. Latter
The cell cycle is split up into four major phases based on proteins are unstable and their cellular concentration cycles
the events unfolding in the cell. During the first gap phase throughout the cell cycle. Accordingly, specific cyclin-CDK
(G1) the proteins are produced that are essential for DNA complexes persist in an active form for a very short period of
replication. The genetic information is then being replicated time after translation, and are then degraded or inactivated
during the synthesis (S) phase. In the second gap phase (G2) by the time that particular phase of the cell cycle completes.
all the components that are necessary for the separation of Activation of specific cyclin-CDK complexes are characteristic
the duplicated DNA during the subsequent mitosis (M phase). for the different cell cycle phases, and drive production of
Cells that are not actively dividing are considered to be in a specific molecules associated with, and necessary for that
quiescent state in the resting phase G0. phase of division. Additional levels of dynamic control are
also provided by CDK inhibitors, which block CDK function
Cell division is necessary for life, but unregulated division is even in the presence of their requisite cyclin.
dangerous and counterproductive. Therefore, the cell has an
impetus for maintaining tight regulatory control over how and Click here to see the online version of this article and
when division takes place. There are two major checkpoints the related antibodies, proteins, and ELISA kits
in the cell cycle. The first choke-point the cell must pass is
References
• Kar: “Unraveling Cell-Cycle Dynamics in Cancer.” in: Cell systems, Vol. 2, Issue 1, pp. 8-10, (2018).
• Coffman: “Cell cycle development.” in: Developmental cell, Vol. 6, Issue 3, pp. 321-7, (2004).
• Jamasbi, Hamelian, Hossain, Varmira: “The cell cycle, cancer development and therapy.” in: Molecular biology reports, Vol. 49, Issue 11, pp. 10875-10883,
(2022).
• Martínez-Alonso, Malumbres: “Mammalian cell cycle cyclins.” in: Seminars in cell & developmental biology, Vol. 107, pp. 28-35, (2021).
• Nagy, Esiri, Smith: “The cell division cycle and the pathophysiology of Alzheimer’s disease.” in: Neuroscience, Vol. 87, Issue 4, pp. 731-9, (1998).
3. Related Pathways | Cell Division Cycle Pathway ©2023 15DNA Damage Repair Pathway
DNA is the carrier of the genetic information that defines reversal (DR), mismatch repair (MMR), and nucleotide
any living being. The genetic code fixed in DNA is crucial excision repair mechanisms. DNA single strand breaks are
for processes on a subcellular scale up to the appearance being mended via base excision repair. Highly mutagenic DNA
and function of the organism as s whole. Nonetheless, DNA double strand breaks finally are repaired through a number of
is constantly exposed to insults from endogenous sources complex pathways that rely on homologous recombination
such as hydrolysis, oxidation, alkylation, or replication errors. (HR) with the sister chromatid (in the S or G2 phase of the cell
In addition, ionizing radiation, UV radiation, and a plethora cycle) or non-homologous end-joining (NHEJ) of both ends
of chemical reagents are external factors that threaten the of the double strand break. The Fanconi Anemia pathway
integrity of DNA. is or particular importance for the repair of DNA interstrand
crosslinks. In case a DNA lesion cannot be repaired in time,
Unlike RNA and proteins, DNA is not being degraded and specialized DNA polymerases enable trans-lesion synthesis
re-synthesized upon damage. Instead, various repair (TLS) in order to prevent the DNA replication fork from
pathways are in existence to assure that the DNA remains stalling. Mutations that render components of these repair
intact. Francis Crick noted in 1974 that “we totally missed pathways non-functional lead to diseases such as xeroderma
the possible role of enzymes in [DNA] repair. I later came to pigmentosum, ataxia telangiectasia, Fanconi anemia, and a
realize that DNA is so precious that probably many distinct predisposition for cancer.
mechanisms could exist.”
Besides, these repair mechanisms are of high interest for
This presage holds true today: over a hundred genes have current targeted genome editing approaches that typically
been characterized since that are involved in an intricate take advantage of the cellular DNA repair machinery.
network of DNA repair pathways. DNA damage can be
repaired via six different pathways depending on the nature Click here to see the online version of this article and
of the lesion: chemical modifications, misincorporated the related antibodies, proteins, and ELISA kits
nucleotides, and cross-links are reverted through direct
References
• Aparicio, Baer, Gautier: “DNA double-strand break repair pathway choice and cancer.” in: DNA repair, Vol. 19, pp. 169-75, (2015).
• Chatterjee, Walker: “Mechanisms of DNA damage, repair, and mutagenesis.” in: Environmental and molecular mutagenesis, Vol. 58, Issue 5, pp. 235-263,
(2017).
• Ray Chaudhuri, Nussenzweig: “The multifaceted roles of PARP1 in DNA repair and chromatin remodelling.” in: Nature reviews. Molecular cell biology, Vol. 18,
Issue 10, pp. 610-621, (2017).
• Bian, Meng, Zhang, Li: “MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment.” in: Molecular cancer, Vol. 18,
Issue 1, pp. 169, (2020).
• Fang, Wu, Zhang, Liu, Zhang: “Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets.” in:
Frontiers in cell and developmental biology, Vol. 8, pp. 160, (2020).
• Burgess, Rose, Boucher, Plowman, Molloy, Fisher, O’Leary, Richard, O’Byrne, Bolderson: “The Therapeutic Potential of DNA Damage Repair Pathways and
Genomic Stability in Lung Cancer.” in: Frontiers in oncology, Vol. 10, pp. 1256, (2020).
3. Related Pathways | DNA Damage Repair Pathway ©2023 16Epigenetics
Epigenetics is defined as heritable changes in gene Histone Modifications
expression that are, unlike mutations, not attributable
to alterations in the sequence of DNA. The predominant
Similarly to DNA methylation, posttranslational histone
epigenetic mechanisms are DNA methylation, modifications
modifications do not affect DNA nucleotide sequence but can
to chromatin, loss of imprinting and non-coding RNA.
modify its availability to the transcriptional machinery. Several
Epigenetic regulation of gene expression appears to have
types of histone modifications are known, amongst which
long-term effects and wide-ranging effects on health. There
acetylation, methylation, phosphorylation, and ubiquitination
is a clear and prescient implication of benefits to both basic
are the best studied and most important in terms of the
science and human health research that stems from a more
regulation of chromatin structure and (transcriptional)
complete understanding of the epigenome. These benefits
activity. 5 While DNA methylation is considered to be a very
have driven researchers to flock this field, and funding
stable epigenetic modification, histone modifications are
organizations have followed suit.
comparably more labile with their levels being maintained by
a balance between histone modifying enzymes, which add or
A large part of epigenetics is controlled by post-translational
remove specific modifications. Aberrant histone modification
modifications on proteins. Methylations, acetylations,
levels result from an imbalance in these modifying enzymes
ubiquitination or phosphorylations lead to changes that for
in diseased tissue, thus correcting the increased or decreased
example influence transcription. Epigenetic modifications
level of a particular enzyme will restore the natural balance in
happen often during an organism’s lifetime; however, these
the affected cells.
changes can be transferred to the next generation if they
occur in germ cells. Paramutation, bookmarking, imprinting,
gene silencing, X chromosome inactivation, position effect,
changeable disorder or phenotypic severity, reprogramming,
Chromatin Remodeling
maternal attributes, carcinogenic processes, teratogenic
effects, regulation of histone modifications, heterochromatin The presence of histones acts as a barrier to protein
states and cloning are known to involve epigenetic processes. access; thus chromatin remodeling must occur for
essential processes such as transcription and replication.
In conjunction with histone modifications, DNA methylation
plays critical roles in gene silencing through chromatin
DNA Modifications
remodeling. Chromatin remodeling is also interconnected
with the DNA damage response, maintenance of stem cell
Covalent attachment of a methyl group to the C5 position
properties, and cell differentiation programs. Chromatin
of cytosine comprises the principal epigenetic modification
modifications have increasingly been shown to produce long-
of DNA. The presence of a methylated cytosine can repress
lasting alterations in chromatin structure and transcription.
transcription by inhibiting the binding of transcription
Recent studies have shown environmental exposures in utero
factors or may promote the binding of other transcriptional
have the potential to alter normal developmental signaling
repressors, including histone-modifying proteins, such as
networks, physiologic responses, and disease susceptibility
histone deacetylases.
later in life during a process known as developmental
reprogramming.
DNA demethylation plays an important role in development
and tumorigenesis in mammals. DNA demethylation,
occurring in primordial germ cells and in early embryos, is
essential for cells to return to a pluripotent state.
3. Related Pathways | Epigenetics ©2023 17Transcription Factors in intracellular metabolism. They (often) utilize cosubstrates
generated by cellular metabolism, thereby providing a
potential link between nutrition, metabolism, and gene
Chemical modifications of histones and DNA, such as histone
regulation.
methylation, histone acetylation, and DNA methylation, play
critical roles in epigenetic gene regulation. Many of the
Click here to see the online version of this article and
enzymes that add or remove such chemical modifications
the related antibodies, proteins, and ELISA kits
are known, or might be suspected, to be sensitive to changes
References
• Hamilton: "Epigenetics: principles and practice." in: Digestive diseases (Basel, Switzerland), Vol. 29, Issue 2, pp. 130-5, (2011).
• Moosavi, Motevalizadeh Ardekani: "Role of Epigenetics in Biology and Human Diseases." in: Iranian biomedical journal, Vol. 20, Issue 5, pp. 246-58, (2017).
• Loscalzo, Handy: "Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)." in: Pulmonary circulation,
Vol. 4, Issue 2, pp. 169-74, (2014).
• Jin, Li, Robertson: "DNA methylation: superior or subordinate in the epigenetic hierarchy?" in: Genes & cancer, Vol. 2, Issue 6, pp. 607-17, (2011).
• Alaskhar Alhamwe, Khalaila, Wolf, von Bülow, Harb, Alhamdan, Hii, Prescott, Ferrante, Renz, Garn, Potaczek: "Histone modifications and their role in epigenetics
of atopy and allergic diseases." in: Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, Vol.
14, pp. 39, (2018).
• Kelly, De Carvalho, Jones: "Epigenetic modifications as therapeutic targets." in: Nature biotechnology, Vol. 28, Issue 10, pp. 1069-78, (2015).
• Bariar, Vestal, Richardson: "Long-term effects of chromatin remodeling and DNA damage in stem cells induced by environmental and dietary agents." in:
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer, Vol. 32,
Issue 4, pp. 307-27, (2014).
• Kaelin, McKnight: "Influence of metabolism on epigenetics and disease." in: Cell, Vol. 153, Issue 1, pp. 56-69, (2013).
3. Related Pathways | Epigenetics ©2023 18Extracellular Matrix
Extracellular matrix (ECM) has both structural and regulatory
roles. Biological regulation by ECM is emerging as a major
research area, driven by several new directions. As a crucial
modulator of cell behavior, ECM has exceptionally strong
relevance and translational implications for human disease,
opening novel opportunities for mechanistic understanding of
disease pathogenesis as well as treatment.
Formation of the extracellular matrix (ECM) requires cells to
secrete ECM proteins. Assembly is achieved by following a
strict hierarchical assembly pattern which begins with the
deposition of fibronectin filaments on the cell surface, a
process known as fibrillogenesis. Cells continue to remodel
the ECM by degradation and reassembly mechanisms, the
dynamic nature of the ECM being particularly apparent during
development, wound healing, and certain disease states.
polarity (stage 1). Depending on contexts, the ECM may
It is estimated that there are over 300 proteins comprising
serve to block or facilitate cell migration (stages 2 and 3).
the mammalian ECM or “core matrisome” and this does not
In addition, by binding to growth factor signaling molecules
include the large number of ECM-associated proteins. Cells
and preventing their otherwise free diffusion, the ECM acts
interact with the ECM through receptors such as integrins and
as a sink for these signals and helps shape a concentration
syndecans, resulting in the transduction of multiple signals
gradient (stage 4). Certain ECM components, including
to regulate key cellular processes such as differentiation,
heparan sulfate proteoglycans and the hyaluronic acid
proliferation, survival, and motility of cells. The ECM has also
receptor CD44, can selectively bind to different growth factors
been shown to bind growth factors such as VEGF, HGF and
and function as a signal coreceptor (stage 5) or a presenter
BMPs which are thought to create growth factor gradients
(stage 6) and help determine the direction of cell–cell
that regulate pattern formation during development. Many of
communication (Lu et al., 2011). The ECM also direct signals
the ECM-regulated cell processes operate via reorganization
to the cell by using its endogenous growth factor domains
of the actin and microtubule cytoskeletons.
(not depicted) or functional fragment derivatives after being
processed by proteases such as MMPs (stage 7). Finally,
Mechanisms of ECM function cells directly sense the biomechanical properties of the ECM,
including its stiffness, and change a wide variety of behaviors
The versatile functions of the ECM depend on its diverse accordingly (stage 8).
physical, biochemical, and biomechanical properties.
Anchorage to the basement membrane is essential for Click here to see the online version of this article and
various biological processes, including asymmetric cell the related antibodies, proteins, and ELISA kits
division in stem cell biology and maintenance of tissue
References
• Hubmacher, Apte: "The biology of the extracellular matrix: novel insights." in: Current opinion in rheumatology, Vol. 25, Issue 1, pp. 65-70, (2013).
• Sottile, Hocking: "Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions." in: Molecular
biology of the cell, Vol. 13, Issue 10, pp. 3546-59, (2002).
• Daley, Peters, Larsen: "Extracellular matrix dynamics in development and regenerative medicine." in: Journal of cell science, Vol. 121, Issue Pt 3, pp. 255-64,
(2008).
• Hynes, Naba: "Overview of the matrisome--an inventory of extracellular matrix constituents and functions." in: Cold Spring Harbor perspectives in biology, Vol.
4, Issue 1, pp. a004903, (2012).
• Taipale, Keski-Oja: "Growth factors in the extracellular matrix." in: FASEB journal : official publication of the Federation of American Societies for Experimental
Biology, Vol. 11, Issue 1, pp. 51-9, (1997).
• López, González, Díez: "Circulating biomarkers of collagen metabolism in cardiac diseases." in: Circulation, Vol. 121, Issue 14, pp. 1645-54, (2010).
• Lu, Weaver, Werb: "The extracellular matrix: a dynamic niche in cancer progression." in: The Journal of cell biology, Vol. 196, Issue 4, pp. 395-406, (2012).
• Lu, Takai, Weaver, Werb: "Extracellular matrix degradation and remodeling in development and disease." in: Cold Spring Harbor perspectives in biology, Vol. 3,
Issue 12, (2012).
• Hamill, Kligys, Hopkinson, Jones: "Laminin deposition in the extracellular matrix: a complex picture emerges." in: Journal of cell science, Vol. 122, Issue Pt 24,
pp. 4409-17, (2010).
• Singh, Carraher, Schwarzbauer: "Assembly of fibronectin extracellular matrix." in: Annual review of cell and developmental biology, Vol. 26, pp. 397-419, (2010).
• Frantz, Stewart, Weaver: "The extracellular matrix at a glance." in: Journal of cell science, Vol. 123, Issue Pt 24, pp. 4195-200, (2011).
3. Related Pathways | Extracellular Matrix ©2023 19You can also read
