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IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production

IR is known to induce EMT in vitro

p53 is activated in response to IR-induced DNA damage

IR paradoxically also promotes tumour recurrence and metastasis

DNA double-strand breaks (DSBs)

cancer cells undergoing EMT acquire invasive and metastatic properties

changes in the tumour microenvironment (TME)

IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism

EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy

Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism

EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis

IR is known to induce stemness and metabolic alterations in cancer cells

transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt

activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47

Loss of E-cadherin is considered a hallmark of EMT

IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells

IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance

sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells

ROS are known to play an important role in IR-induced EMT

High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis

hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT

Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells

Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion

IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion

NF-κB signalling that promotes cell migration

ROS promote EMT to allow cancer cells to avoid hostile environments

HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.

Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α

levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)

IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation

IR induces vascular damage that causes hypoxia

ROS is implicated in IR-induced HIF-1 activation

IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1

IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway

The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion

TGF-β signalling has been shown to play a crucial role in IR-induced EMT

AP-1 transcription factor is involved in IR-induced TGF-β1 expression

Wnt/β-catenin signalling is also implicated in IR-induced EMT

Notch signalling is known to be involved in IR-induced EMT

IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail

PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT

EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK

ROS and RNS are also implicated in IR-induced EGFR activation

IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT

IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion

CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour

Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis

identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules

CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH

Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,

signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT

microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451

Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes

EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties

Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype

TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells

some CSC subpopulations arise independently of EMT

IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma

Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production

IR has been shown to induce reprogramming of differentiated cancer cells into CSCs

In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties

IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells

EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties

STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells

Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers

metabolic reprogramming

HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism

metabolic reprogramming

tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis

occurring within the same tumour

CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen

mitochondrial function is crucial for maintaining CSC functionality

cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia

HIF-1 then enhances glycolysis

CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells

lactate transporter, monocarboxylate transporter (MCT)

nutrient microenvironment

Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle

MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS

metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells

bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production

the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers

HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism

regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells

HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch

HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity

STAT3 has been implicated in EMT-induced metabolic changes as well

TGF-β and Wnt play important roles in the metabolic alteration of cancer cells

Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness

EMT, invasion, metastasis, and stemness

pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes

decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis

LDH catalyses the bidirectional conversion of lactate to pyruvate

High levels of LDHA are positively correlated with the expression of EMT and CSC markers

IR has been shown to induce metabolic changes in cancer cells

IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate

IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate

IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment

IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis

Lactate can activate latent TGF-

lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis

promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP

tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.

immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)

immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)

intrinsic immunogenicity or induce tolerance

cancer immunoediting’

three phases: 1) elimination, 2) equilibrium, and 3) escape.

The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).

IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response

IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP

TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling

MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis

IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis

IR-induced Snail increases MMP-2 expression to promote EMT

Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness

IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism

Metabolic alterations

oncogenic metabolism

elicit various changes in the TME

Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms

Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells

metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress

Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells

Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells

Reverse Warburg Effect

secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation

oxidative stress has an important role in the initiation and preservation of breast cancer progression

cancer preventive role of healthy mitochondria

the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.

Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants

cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts

Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin

However, diets rich in antioxidants have fallen short in sufficiently preventing cancer

obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.

It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells

It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice

hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence

Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction

Studies of similar meshes that are used in hernia repair have demonstrated that all polypropylene meshes induce a prolonged inflammatory response at the site of implantation

the long-term presence of activated inflammatory cells, such as macrophages at the mesh tissue interface, can impact negatively the ability of the mesh to function as intended.

All M1 proinflammatory and M2 proremodeling cytokines and chemokines were increased in mesh explants as compared with nonmesh tissue (Table 3Table 3), which indicated a robust, active, and ongoing host response to polypropylene long after implantation

Comparison of the ratio of the M2 proremodeling cytokines (IL-10+IL-4) with the M1 proinflammatory cytokines (TNF-α+IL-12p70) revealed a decrease in mesh explants as compared with controls (P = .003), which indicated a shift towards a proinflammatory profile.

Mesh explants contained a higher number of total cells/×200 field when compared with controls (682.46 ± 142.61 cells vs 441.63 ± 126.13 cells; P < .001) and a lower ratio of M2:M1 macrophages (0.260 ± 0.161 cells vs 1.772 ± 1.919; P = .001), which supported an ongoing proinflammatory response.

the host response was proportional to the amount of material in contact with the host

A persistent foreign body response was observed in mesh-tissue complexes that were excised from women who required surgical excision of mesh months to years after mesh implantation

The host response was characterized by a predominance of macrophages with an increase in both proinflammatory and proremodeling cytokines/chemokines along with increased tissue degradation, as evidenced by increased MMP-2 and -9

Mesh-tissue complexes removed for mesh exposure had increased pro–MMP-9 that indicated a proinflammatory and tissue destruction–type response

The presence of macrophages, elevated cytokines, chemokines, and MMPs in tissue-mesh complexes that were excised from patients with exposure or pain suggests that polypropylene mesh elicits an ongoing host inflammatory response

In the presence of a permanent foreign body, the implant is surrounded with a fibrotic capsule because it cannot be degraded

For hernia meshes, if the fibers are too close (<1 mm), the fibrotic response to neighboring fibers overlaps, or “bridges,” and results in “bridging fibrosis” or encapsulation of the mesh

Gynemesh PS has a highly unstable geometry when loaded that resulted in pore collapse and increasing stiffness of the product

mesh shrinkage (50-70%) has been described to occur after transvaginal insertion of prolapse meshes

chronic hypoxia

acute hypoxia

Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth

HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)

When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways

c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.

mTOR can also promote stabilization and HIF transcriptional activity

hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment

Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration

Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments

The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group

Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals

interrupting cell proliferation, inducing apoptosis

[155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha

resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha

prevents cytokine-induced vascular leakage and tumor metastasis

The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors

surgery per se can promote cancer metastasis through a series of local and systemic events

surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers

After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear

infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients

Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis

Surgery-induced cancer metastasis has been well established in animal models

tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis

the surgical resection of primary tumors is beneficial is controversial

CTCs abruptly increase just after surgery

Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer

excessive glucocorticoids negatively modulate immune functions

immune surveillance against tumors is considered to be impaired by surgical stress

In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla

NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids

In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases

primary tumors may secrete angiogenic inhibitors as well as angiogenic activators

second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.

double-edged sword

HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity

neutrophils play various roles in the initiation and progression of cancer

NETosis

many inflammatory and neoplastic diseases

formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1

NETosis has been highlighted as an inflammatory event that promotes cancer metastasis

Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves

A series of these events is called NETosis.

neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins

innate immune response against infection

Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells

two types of NEToses, suicidal (or lytic) NETosis and vital NETosis

Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)

Since neutrophils die during this process, it is called suicidal NETosis.

vital NETosis

vital NETosis occurs independently of ROS production

Vital NETosis can be induced by Gram-negative bacteria. LPS

NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia

neutrophils actively undergo NETosis in the tumor microenvironment

Hypoxia

NETosis plays a pivotal role in noninfectious autoimmune diseases,

cytokines

tumor-derived proteases

tumor exosomes

NETosis generally actively progresses in the tumor microenvironment.

the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.

NETosis is a defense system to protect the body from invading pathogens

when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences

plasma levels of NETosis markers are elevated after major surgeries

local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases

NETs promote metastasis at multiple steps

NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells

NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow

NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)

neutrophil elastase, matrix metalloproteinase 9, and cathepsin G

NETs also promote the intravasation of cancer cells

millions of tumor cells are released into the circulation every day,

NETs can wrap up CTCs with platelets

β1-integrin plays an important role in the interaction between CTCs and NETs

NET-platelet-CTC aggregates.

After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late

NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions

NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells