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glioblastoma, it was found that binding of CD95 to its homologous ligand CD95L demonstrated
atypical CD95 function that resulted in the promotion of tumour growth through inducing inflammation, regulating immune cell homoeostasis, promoting proliferation and maintenance of cancer
cells(14). Further, studies have shown that expression of caspase- 8 or its function can be impaired
by genetic mutations, epigenetic mechanisms and, more recently, through phosphorylation of
caspase- 8 gene through tyrosine kinases, in various cancers, including colorectal, head and neck
carcinomas, retinoblastoma and small lung carcinoma(15, 16).
24.6 Enabling Replicative Immortality
Cellular senescence is a cellular state during which cells remain metabolically active but withdraw
from the cell cycle and limit the proliferative capacity of clonal cell lineages in the absence of routine growth arrest(17). Clinical evidence demonstrates that an intact senescence response prevents unregulated growth and malignant transformation(17). The direct mechanism or pathways
of senescence are not entirely understood but have been associated with cell- cycle arrest in the G
phase via multiple pathways, including the p53- p21 pathway, p16- RB pathway, formation of
or G
2
the DREAM complex through inhibition of cyclin- dependent kinase (CDK) complexes and promotion of senescence- associated secretory phenotype (SASP) gene through NF- κB(18). The principal
cause of senescent stress is DNA damage(18). However, through genetic and epigenetic causes,
mechanisms of senescence can fail, leading to ongoing oncogenic activation and growth of clonal
cell lines, thereby enabling immortal replication(2, 3, 17).
Senescence can also arise due to the usual shortening of telomeric DNA, resulting in irreversible
cell- cycle arrest. Telomerase is a large ribonucleoprotein complex responsible for the maintenance
of telomeres. Telomerase upregulation or reactivation is critical in over 90% of cancers, resulting in
continual oncogenesis (19). However, the mechanisms governing telomerase gene (hTERT)
expression in cancer remain understood and continue to be a significant focus of research(19).
1
24.7 Inducing/Accessing Vasculature
Malignant cells require oxygen and nutrients to survive and proliferate(3, 20, 21). As such, they
must reside near blood vessels to access the blood circulation system(3). Tumour vascularisation
occurs through several distinct biological processes, known as angiogenesis, that vary between
tumour type, anatomic location and within the same cancer tissue(21). These processes are a balance between angiogenic promoters and inhibitors (Table24.3)(20, 21). The initiation of tumour
vascularisation has been termed the angiogenic switch, in which pro- angiogenic signalling is dominant and is inducted by hypoxia(21). Angiogenesis modulators are secreted by endothelial cells,
tumour cells and the surrounding stroma. Tumour vasculature is molecularly distinct from normal
vessels and responds to environmental cues by transcriptional regulation of gene expression(21).
The core gene signature includes VEGFR2, TIE1 and TIE2, central regulators of pro- angiogenic
vascular endothelial growth factor (VEGF) and angiopoietin signalling (21). Further, CLEC14A,
CD93, endosialin and thrombomodulin are also considered part of the core gene signature and are
upregulated in tumour vessels(21).
New capillaries can bud from parental vessels through a process known as sprouting angiogenesis and are inducted by VEGF (21). The developing sprout then connects with other vessels
through anastomosis. An alternative mechanism for neo- vascularisation in tumours is
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Table24.3 Examples ofknown angiogenic factors.
Promoters Inhibitors
1- Butyryl glycerol 2- Methoxy- estradiol
Acid fibroblast growth factor ADAMTS- 1
Adenosine Angiostatin
Angiogenin Antiangiogenic antithrombin III
Angiopoietin- 1 (Ang1) Angiopoietin- 2
Collagen Cartilage- derived inhibitor
Del- 1 Decorin
Entactin Endostatin
Epidermal growth factor Fibronectin fragment
Ephrins Heparinases
Fibroblast growth factor Human chorionic gonadotropin (hCG)
Fibronectin Interferons α, β, γ
Follistatin Interleukin- 1, - 4, - 12
Granulocyte colony- stimulating factor Metalloproteinase inhibitors (TIMPs)
Interleukin- 8 Platelet factor 4
Nicotinamide PEDF
Platelet- derived endothelial growth factor Retinoids
Prostaglandins E1 and E2 Tissue inhibitor of metalloproteinases– 1, 2, 3
Tumour necrosis factors- alpha Vascular endothelial growth inhibitors (VEGI)
Vascular endothelial growth factor Vasculostatin
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Source: Adapted from(20).
vasculogenesis, mediated by the recruitment of endothelial progenitor cells (EPCs) or bone
marrow- derived hematopoietic cells, forming new vessels to support tumour growth (21).
Aggressively growing tumour cells can form vessel- like structures through vascular mimicry.
These structures are formed without the contribution of endothelial cells and represent an alternate channel for tumour cells to source blood supply and nutrients. Vascular mimicry has been
seen in melanoma, glioma, head and neck cancer and lung cancer(21). The structural configuration of blood vessels in normal tissues is also absent in tumours. Tumour vessels are seen to spread
without any organisation, following tortuous paths and changing in diameter(20). An imbalance
in angiogenic factors such as VEGF and angiopoietins is the main reason for the chaotic structure
seen in tumours(20).
24.8 Activating Invasion andMetastasis
Metastasis is a complex, multistep process still yet to be understood entirely. Metastasis is initiated
by disseminating cancer cells from the primary site of tumour growth and intravasate into the
systemic circulation to finally extravasate and colonise a secondary site (Figure24.2)(3, 22, 23).
The invasion and metastatic events begin with the process of dissemination, which is enabled by
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Primary Tumour site
Lymphocyte
ECM
CAF
RBC
Blood vessel
Tumour secreted factors
Macrophage
NK cell
CTCs
Tumour cell
Exosome
Intravasation
Invasion
Metastatic site
Metastatic colonisation
Micrometastasis
Extravasation
Pre-metastatic niche
Figure24.2 Key steps of metastasis. Source: Adapted from Sulekha Suresh and Guruvayoorappan(22).
the epithelial– mesenchymal transition (EMT)(22). The EMT program is a spectrum of transitional
changes between epithelial and mesenchymal prototypes(23). The loss of E- cadherin and reduced
expression of claudin and occludin are key events that trigger EMT initiation and promotion of
disruption of apical tight junction between cells(22, 23). Further, the complexity of the stromal
component of the tumour microenvironment (neutrophils, cancer- associated fibroblasts and regulatory T cells (Tregs)) disrupts matrix metalloproteinases (MMPs), which leads to the loss of basement membrane, which in turn allows direct invasion of tumour cells into the stromal
environment(22). For example, studies have shown that interleukin- 6 (IL- 6) secreted by adipocytes in the stromal microenvironment stimulates breast cancer invasion(24).
Intravasation involves invading disseminated tumour cells through the basement membrane to
organs via the lymphatic or blood vasculature. This process is considered a critical rate- limiting
step, whereby the number of circulating tumour cells is determined through the mediation of carbohydrates, lipids and proteins(22, 23). For example, the interaction between α2β1integrin receptor and glycosphingolipids facilitates prostate cancer cells’ metastatic properties (22). Further,
studies have shown that overexpression of VEGF by tumour cells can disrupt the endothelial barrier, facilitating endothelial transmigration(22).
Circulating tumour cells are highly invasive and proliferative, primarily tumour cells. However,
primary tumour cells must overcome several barriers to colonise a distant site. It is the interaction
between circulating tumour cells and microenvironment components that determine the survival
and extravasation ability (23). Most circulating tumour cells die when transported in circulation,
primarily due to stress, lack of growth factors and cytokines. It is becoming apparent that neutrophils play an essential role in cell- cluster formation, improving survival chances(22, 25). These complexes have been shown to have increased metastatic potential in breast cancer and are thought to be
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24.10 Avoiding Immune Destruction
driven in part by cytokines such as IL- 6 and IL1B expressed by neutrophils(25). Further, interactions
between circulating tumour cells and platelets form a coating shield, preventing immune complexes’
detection. The arrest of circulating tumour cells at a distant site is fundamental to metastatic progression. A suggested theory behind this process involves sequential intravascular clustering, where
the adhesive capability of the tumour cells increases(22). Many tumours arrest in the first capillary
bed they encounter. In contrast, others demonstrate organ tropism, which may be due to the expression of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the
mand oncotic site(22, 23). Once halted within the microvasculature, hemodynamic forces exerted
by blood plasma flow force the clusters to undergo cytoplasmic fragmentation, eventually generating
interaction with immune cells. This interaction has been thought to potentially impact extravasation
and develop metastatic niche formation in a distant site(22, 23). Thrombus formation is believed to
support tumour cell extravasation via fibronectin- mediated integrin activation mechanism. After
successful extravasation, integrins interact with the extracellular matrix in the perivascular tissue,
and this integrin– matrix interplay determines the growth of the metastatic niche(23).
24.9 Reprogramming Cellular Metabolism
Metabolic reprogramming in cancer cells refers to the ability of cancer cells to modify their metabolism, increasing the absorption and use of carbohydrates, lipids and proteins that are mediated by
growth factors, hypoxia- inducible factors, dysfunction of tumour suppressor genes to provide a protumourigenic response(2, 3, 26). Increased glucose uptake and lactate production in the presence
of oxygen, regardless of cancer cells’ anabolic and catabolic needs, has been a cancer trademark for
almost a century. This process occurs via the coupling of NAD/NADH between glyceraldehyde
phosphate dehydrogenase and LDH(26). Further mitochondrial uncoupling provides an essential
source of NAD in the cytosol, thereby increasing glycolytic effects and promoting proliferation(26).
Clinically, this mechanism has been utilised via positron emission tomography to identify tumour
cells that preferentially take up F- fluorodeoxyglucose, a non- metabolisable derivative of glucose.
During carcinogenesis, reprogramming of lipid metabolism results from increased fatty acid uptake,
de novo lipogenesis and altered lipid storage. CD36, fatty acid transport protein family (FATPs), and
plasma membrane fatty acid- binding proteins all exacerbate cancer cells’ aggressiveness, growth
and survival(26). Further, cancer cells need to maintain correct protein synthesis to support biomass production. Glutamine uptake through the SLC1A5 transporter shows that cancer cells
depend on this amino acid, which is utilised as an intermediate for the TCA cycle(26).
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24.10 Avoiding Immune Destruction
Tumour development and its survival are aberrantly governed by the interplay of cancer cells,
normal stromal cells and host defence mechanisms. Malignant tumours express various molecules
the immune system may recognise as foreign antigens(27, 28). However, due to genetic instability,
constant tumour cell division can generate cells with reduced immunogenicity that can avoid
immune elimination. Tumours can also use an interplay of regulatory cells (CD4
Tregs), present defective antigens by downmodulating antigen processing machinery affecting the
major histocompatibility complex (MHC) I pathway inhibiting dendritic cell maturation and utilise immune suppressive mediators such as TGF- β, TNF- α, IL- 1 and IL- 6 within the tumour micro-
environment to evade immune mechanisms(27, 28). Further, most tumour cells fail to express
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+
CD25+FoxP3+
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costimulatory molecules and can induce tolerance in T cells by engaging the T- cell receptor. They
can shift the balance from Th1 to Th2 via TGF- β and IL- 10- dependent manner and avoid immune
destruction(28). Understanding these processes provides further avenues for developing immunotherapy in cancer treatment.
24.11 Genomic Instability
Genomic instability favours carcinogenesis as it increases the chances of acquiring oncogenic
mutations, enabling the onset of cancer hallmarks(2, 3). Mainly, hereditary cancers result from
mutations in DNA repair genes that drive cancer development. Chromosomal instability (CIN) is
the major form of genomic instability in human cancers, both hereditary and sporadic. It refers to
the rate at which chromosome structure and number change over time in cancer cells compared
with normal cells (29). Other genomic instabilities include microsatellite instability (MSI),
whereby the expansion or contraction of the number of oligonucleotides repeats present in microsatellite sequences and genomic instability associated with increased frequency of base- pair
mutations(29). In hereditary cancers, both CIN and non- CIN forms of genomic instability have
been linked to mutations in DNA repair genes(29). For example, mutations in DNA mismatch
repair genes lead to MSI in hereditary non- polyposis colon cancer (30). Cancers linked to CIN
include germline mutations in breast cancer susceptibility 1 (BRCA1), BRCA2, partner and localiser of BRCA2 (PALB2), BRCA1- interacting protein (BRIP1) and Fanconi anaemia genes have all
been linked to the repair of DNA double- strand breaks or DNA interstrand cross- links, predisposing the development to breast, ovarian cancer, leukaemias and lymphomas(29, 31). Identifying
these mutations provides significant support for the mutator hypothesis that suggests that
genomic instability is present in precancerous lesions and ultimately leads to malignant transformation by increasing the spontaneous mutation rate(29). Genomic studies have also revealed that
the TP53 tumour suppressor and DNA damage checkpoint gene are the most frequently mutated
genes(29, 32). Loss of p53 function results in the proliferation of severely damaged genomes and
the continuation of oncogenic mutations(32). Further, a rapidly emerging paradigm in genomic
instability and carcinogenesis is the modulation of genes and pathways by microRNAs (miRNA).
Recent studies have shown that miRNAs are key players in regulating the DNA damage/repair
network and can ultimately lead to CIN(33). Studies have suggested that progressions of hepatocellular carcinoma caused by accumulating extra copies of DNA and gene mutations in cells are
due to instability provoked by SSRP1 dysregulation via miR- 497(33). It has also been shown that
miRNA plays a crucial role in the maintenance of microsatellite loci and that the dysregulation of
miRNA through targeting mismatch repair gene family members is likely to induce MSI (33).
Further studies are needed to elucidate the complete mechanisms of modulating genomic
instability.
24.12 Tumour- Promoting Inflammation
Tumour- promoting inflammation has been considered an enabling characteristic of cancer(3).
Inflammatory cells and mediators are present in the tumour microenvironment, functioning in
biological processes such as tissue remodelling and angiogenesis to promote cancer development.
Mutations in oncogenes, such as protein tyrosine kinase RET, RAS and MYC, may lead to an
intrinsically inflammatory microenvironment. In contrast, extrinsically, infections and lifestyle
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may induce inflammation during tumourigenesis(34). Tumour infiltrating cells include tumourassociated macrophages (TAMS), dendritic cells (TADC), lymphocytes (natural killer cells, T lym-
phocytes and B lymphocytes) and inflammatory cytokines and chemokines(34). IL- 6 is one of
the most studied pro- inflammatory cytokines shown to play a role in oncogenesis by inhibiting
apoptosis and activating several signalling pathways related to cell proliferation, migration and
angiogenesis(34). TAMS can also produce it and has been shown to promote EMT transition in
epithelial ovarian cancer(34). Microbial infections such as hepatitis B and C and autoimmune
diseases that lead to chronic inflammation can also trigger cancer formation due to the increased
numbers of immunosuppressive cells, including M2macrophages, Treg cells and cytokines(34).
These changes have been reported to promote the activation of oncogenes, DNA and protein
damage, the release of ROS and affect multiple signalling pathways, including NF- κB, K- RAS and
P53, leading to and enabling the acquisition of cancer hallmarks(34).
24.13 Emerging Hallmarks andEnabling Characteristics
24.13.1 Unlocking Phenotypic Plasticity
Increasing evidence shows that unlocking the normally restricted capability for phenotypic plasticity to evade or escape from terminal differentiation is critical for cancer progression (2).
Unlocking phenotypic plasticity and disrupting normal differentiation of progenitor cells through
dedifferentiation of mature cells back to progenitor cells, blocking differentiation from progenitor
cell states to freeze development, and transdifferentiation to alternative cell lineages into different
cell lines have been shown to progress malignancy in cancer cells(2). Examples of these pathways
are seen in colon carcinogenesis, acute promyelocytic leukaemia and pancreatic ductal adenocarcinoma, and as such, this characteristic has been proposed as an emerging hallmark of cancer(2).
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24.13.2 Senescent Cells
Evidence suggests that the SASP- evoked chronic inflammatory microenvironment can promote
tumourigenesis(18). This has been seen in ovarian tumourigenesis, where the RAS oncogeneactivated chemokine growth- regulated alpha protein has been shown to reprogram the stromal
microenvironment by inducing senescence of normal fibroblasts(18). In the case of colon tumour
cells, senescent fibroblasts have been shown to release SASP factors that activate WNT signalling
and increase tumour stem cell properties(18). While more research is required, there is the suggestion that other stromal cells within the tumour microenvironment will prove to undergo senescence, thereby modulating cancer hallmarks and consequent tumour phenotypes(2).
24.14 Emerging Enabling Characteristics
24.14.1 Non- mutational Epigenetic Reprogramming
It has been suggested that another independent mode of genome reprogramming may be purely
associated with epigenetic changes in gene expression and likely enable cancer cells’ capability to
unlock phenotypic plasticity(2). There is increasing knowledge that intratumoural heterogeneity
is essential in generating phenotypic diversity(35). This process has been described in human oral
squamous cell carcinomas, whereby cancer cells at the invasive margins adopt a partial EMT state
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but express other EMT- defining genes that are not expressed in the central core of the tumour(35).
Furthermore, it has been shown that to enhance the tumour- promoting activities, stromal cells
such as cancer- associated fibroblasts, innate immune cells and endothelial cells are epigenetically
reprogrammed, distinct from that of genomic DNA instability and mutation, upon recruitment to
the tumour microenvironment(35).
24.14.2 Polymorphic Microbiomes
Recent evidence suggests that the microbiome in different tissues or populating incipient neoplasia can contribute to or interfere with acquiring other cancer hallmarks beyond genome mutation
and immunomodulation(2, 36). The gut microbiome has been long studied, and bacterial binding
to colonic epithelium has been shown to stimulate epithelial proliferation in neoplastic cells and
contribute to the hallmark proliferative signalling capability(36). As this area of research continues, there will be further cases to show the features of polymorphic microbiomes to enable the
acquisition of hallmark capabilities.
24.15 Summary
The development of cancer is a complex phenomenon. It is now well understood that cancer development occurs over a multistep process and requires cells to acquire ‘hallmark’ characteristics that
are essential for neoplastic growth, which are ‘enabled’ by supporting factors that empower the
cells to develop these qualities. Although advancements in genomic technology have greatly
helped us identify tumour- promoting pathways and genes, the current understanding of the entire
tumour makeup is still incomplete. The broadened discipline of cancer genomics needs to elucidate the dynamic coevolution between cancer cells and the immune system. Further technological
innovation is required to achieve these breakthroughs and provide additional therapeutic targets
in cancer treatment.
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25
Host Defences Against Cancer
Andreia Bufalino
Oral Medicine, Department of Diagnosis and Surgery, School of Dentistry, São Paulo State University– UNESP,
Araraquara, São Paulo, Brazil
25.1 Introduction
The tumour microenvironment (TME) concept has revolutionised our understanding of tumourigenesis.
It highlights the complex interplay between cancer cells, the non- cancer cells that comprise the
TME and the extracellular matrix. This interplay is responsible for the acquisition of the hallmark
capabilities of cancer cells, as well as for the promotion of tumour progression and metastasis(1).
Therefore, the TME plays an essential role in the development of cancer, from the initial stages of
initiation and progression to the later stages of metastasis and recurrence(2). In this context, it is
hypothesised that tumours arise with similar frequency to that of infections by external pathogens,
but the immune system constantly recognises and neutralises these tumours based on the
expression of tumour antigens. On the other hand, active evasion by cancer cells from attack and
elimination by immune cells has been described(3). This capability highlights the dichotomous
role of an immune system that both antagonises and enhances tumour development and
progression(4–6).
In this sense, the identification of the participation of these cells in tumour progression– including
their possible biomarkers– is of utmost importance for the development of new therapeutic as
well as diagnostic strategies in cancer care.
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25.2 Cancer Immunosurveillance andImmunoediting
The theory of immunological surveillance is based on the idea that the immune system is constantly on alert, monitoring cells and tissues for any signs of alteration. These cells are then identified and eliminated, preventing the development of tumours(5). Several observations support this
theory. For example, individuals with weakened immune systems, such as those with acquired
immunodeficiency syndrome (AIDS), are more susceptible to developing cancer than those with
healthy immune systems. Cancer- fighting treatments such as immunotherapy rely on the body’s
immune system to fight off cancer cells(7).
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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