Introduction

Neoplasm or cancer is the unrestricted growth, expansion, and spread of cells, triggered by stimulation of oncogenes and/or growth factors, abrogation of tumour suppressors and/or cell cycle check points, disparities in redox signalling with sequential indulgence of multiple genes and signalling pathways, characterised by deranged cellular architecture, and altered genomic plus metabolic signature. Cancer is the second leading cause of death globally, accounting for one in six deaths. It was responsible for 8.8 million deaths in 2015 [1].

Metabolic inclination of cancer cells towards an accelerated rate of aerobic glycolysis (Warburg’s hypothesis) in par with their uncontrolled proliferation (to meet energy requirements) creates a hyperglycemic microenvironment prone to oxidative stress and glycation, in addition to related inflammation [2, 3]. The by-products of enhanced glycolytic flux called advanced glycation end products (AGEs) have been implicated in the progression and invasion of cancers [4, 5]. Several studies have reported the presence of different types of protein-AGEs namely, argpyrimidine and carboxy methyl lysine [6] and DNA-AGEs like CEdG (N2-(1-carboxyethyl)-2′-deoxyguanosine) in cancer tissues, circulating autoantibodies to these glycated conjugates of proteins and nucleic acids [7, 52].

Non-enzymatic glycation of haemoglobin alters its structure and function, increasing its affinity for oxygen and thereby reducing the delivery of oxygen to tissues. This glycated haemoglobin could diminish oxygen supply to tumour tissues, resulting in hypoxia [50]. Hypoxia enables cancer cells to overcome nutritive deprivation by up regulated glycolysis to escape the hostile environment, by altering the genome and proteome of neoplastic cells. Hence, hypoxia favours hyperglycemic milieu for AGEs production and the modification of molecular milieu including vascular components by AGEs in turn result in hypoxia [54].

Altogether, glycated proteins or AGEs by themselves have the potential to support and augment cancer related cellular and molecular events, besides perpetuation of cancer development via RAGE binding.

RAGE-Dependent Effects of AGEs

RAGE is comprised of three extracellular domains, V, C1, and C2, a trans-membrane helix, and a short cytoplasmic tail. Receptor-mediated effects of AGEs involve interaction with RAGE V domain [55]. Major AGEs found in tissues and plasma (in cancer and physiological conditions) that are also ligands of RAGE include CML, CEL, and argpyrimidine. This interaction is concomitant with chronic inflammation and cancer, besides diabetic complications and Alzheimer’s disease.

AGE modifications observed in cancer tissues include [48]:

  • Pyrraline

  • Imidazolone A & B

  • Argpyrimidine (a MG modification)

  • Fructosylysine

  • Methyl glyoxal lysine dimer

  • Nε-(carboxyethyl)lysine (CEL)

  • Nε-(carboxymethyl)lysine (CML)

The preferential AGE modifications identified in cancer tissues include CEdG-DNA adducts, argpyrimidine, and CML-modified protein adducts. These AGE adducts have been reported both in tumours and adjacent normal tissues of the breast, colon, and other cancers, indicative of their role in the onset as well as progression of cancers [6]. AGE-RAGE signalling of stromal components has also been implied in cancer growth.

Argpyrimidine modification of HSP-27 (heat shock protein) plays a role in suppressing cyt-c-induced caspase activation, and its inhibition was found to sensitise cancer cells to drug-induced apoptosis. Nuclear, cytoplasmic, and extracellular argpyrimidine modifications have been observed in tumours. Intracellular AGEs cause DNA mutagenesis and protein dysfunctions resulting in the abnormal genome and proteome, eliciting disruption of growth checkpoints for cancer initiation and survival [56], unlike extracellular AGEs acting upon tumour initiation and spread via RAGE binding [16]. This is further established by the glycoxidative lesions identified in lymphocyte DNA from cancer patients [7] and augmented expression of AGEs, RAGE, and NF-ķB predominantly in tumour tissues of invasive carcinoma than the corresponding control [48, 57].

Glycated and diabetic HDL have been observed to promote cancer survival, growth, and invasion in breast cancer [83] and extracellularly as a cytokine and damage-associated pattern molecule (pathological function), indicative of its potent role in promoting malignancies, only upon cellular release [84]. Majority of cancer cell death cause HMGB1 release, thus intensifying RAGE signalling alongside AGEs, making the tumour phenotype aggressive, therapy resistant and eliciting tumour resurgence [85].

S100 family of small molecular weight calcium-binding proteins is prevalent in a wide variety of inflammatory diseases and upregulated in many cancers. They are expressed by neutrophils, macrophages, lymphocytes, and dendritic cells. S100 proteins that bind RAGE with reported presence in cancer tissues include S100A4, S100A6, S100A7, S100A8/9, S100A11, S100B, and S100P. S100A8/9, a key pro-inflammatory mediator in acute and chronic inflammation, depicts elevated levels in chemical induced carcinogenesis via RAGE induction, eliciting a positive regulatory loop of chronic inflammatory setting essential for tumour promotion [86,87,Osteopontin, RAGE/Ligands, and Cancer

In addition to RAGE, AGEs are known to up regulate the expression of osteopontin [115, 116], which binds with cell membrane bound integrin and CD44 and sets up a signalling cascade contributing to inflammation and tumour development [117, 118]. Osteopontin (OPN), a vital protein component of extracellular matrix, has important physiological functions like the regulation of immune response, bone metabolism, and pathological functions like proliferation, angiogenesis, and invasion of cancers [119, 120]. OPN transactivates normal mammary fibroblasts to tumour promoting fibroblasts via TGF-β1, thereby aiding breast cancer progression and metastasis [118, 121]. Augmentation of OPN expression is seen in patients with TNBC [122, 123], a biologically aggressive tumour with Warburg’s glycolytic phenotype with high RAGE expression and also in HER2 over expressing breast cancers [124]. Both RAGE and OPN expression levels are elevated proportionately with metastatic grade, concomitant with poor prognosis [102, 125, 126]. AGEs increase both RAGE and OPN expression levels [116], and the rise in OPN is neutralised by anti-RAGE antibody, implicating the involvement of RAGE in AGE driven OPN expression [115]. HMGB1/RAGE/ OPN/EGR-1 pathway has been implicated in inflammation and angiogenesis of proliferative vitreo-retinal disorders [127] (the modulation of OPN by AGEs and HMGB1 in cancer tissues still needs to be evaluated).

OPN induces nuclear HMGB1 acetylation via activated NOX and abrogated HDAC expression and facilitates its translocation to cytoplasm enabling collagen expression. HMGB1 promotes collagen biosynthesis via RAGE/PI3K/AKT pathway [128, 129]. Though proteosomal degradation of extracellular matrix is required for cellular invasion in cancers, recent evidence reveals the vital role of type-I collagen in paving way for cell migration during invasion [130]. OPN also causes an upsurge in HMGB1 expression and release from tumour and non-tumour cells. OPN prompts HIF-1α and VEGF through PKC/PI3K/Akt pathway [131,132,133] and stimulates breast cancer growth through p70S6k dependent ICAM-1 expression by MEK/ERK pathway [134] and activation of JAK/STAT signalling [135]. OPN via ERK1/2 and p38 MAPK facilitates AP-1-mediated enhanced COX-2 levels and hence PGE-2, contributing to endothelial cell motility, migration, and cancer growth [136, 137]. Hahnel and colleagues have described that osteopontin knockdown elicits diminished survival, enhanced apoptosis, and improved radio sensitisation of MDA-MB-231 cancer cells [138].

figure a

Both AGEs and HMGB1 might serve to augment osteopontin via RAGE dependent cell signalling in cancer tissues and adjacent non-tumorous micro milieu. In addition, several genes stimulated downstream RAGE and in cancer are also regulated by osteopontin and vice versa, all of which require further in-depth studies into the molecular mechanisms concerned.

The comprehensive role of RAGE-ligand signalling network in deriving the absolute hallmarks of cancer progression and the intricately woven multiple molecular signal cues forming the framework of progressive cancers have been discussed in detail.

RAGE/Ligands—Cancer Stem Cells and Hallmarks of Metastatic Cancers

CSCs with the pluripotency to generate cancer cells at any period of time remain in small groups, which can be easily missed by regular oncotherapy regimen. They are said to be responsible for the genesis, metastasis, and resurgence of cancers, even many years after treatment [139]. Normal cells expressing CSC markers are associated with cancer risk [140]. Though few in numbers, the self-replicative potential of CSC is hard but equally important to be targeted with therapeutics for successful treatment of cancers, prevention of metastasis, and recurrence. Hence, it is crucial to understand the interplay between the malignant/metastatic tumour niche, RAGE-ligand signal axis, and stem cell pathways in cancers. All these molecular interactions emerging as the complete hallmarks of cancer from its initiation to invasion are also discussed.

Tumour Micromilieu in Metastasis

Paget’s seed and soil theory emphasises the vital role of micro milieu in providing a favourable environment for cancer cells in distant organs, eliciting metastasis [141]. The non-tumorous niche composed of stromal cells, cancer-associated fibroblasts, and tumour-associated macrophages contributes major part to the promotion of metastasis and tumour relapse [142]. Besides causing cancer cell death, the chemotherapeutic drugs possibly evoke differential genetic and functional alterations in normal stromal cells or tumour micromilieu, which could potentially determine the propensity of cancer recurrence post chemotherapy. HMGB1 released from necrotic cells and oxidative stress generated in tumour milieu following oncotherapy (section “Evasion of Immune Suppression”) all contribute towards chemo resistance, cancer cell survival and recurrence [104]. Cancer associated fibroblasts (stromal cells) are also reported to express HMGB1, S100A4 and AGEs, which signifies the role of stromal cells in activating RAGE in cancer tissues. This underlines the use of AGE/HMGB1/S100 inhibitors following conventional cancer treatment in preventing therapy resistance, metastasis, and recurrence of cancers.

Cancer Stem Cells and EMT

Abrogation of CSC has been recommended as an essential component of cancer therapeutics, owing to their dynamic role in the survival and metastasis of cancers [139]. Wnt/β-catenin, Notch, and hedgehog pathways are involved in the differentiation and regeneration of normal stem cells; their dysregulation drives tumour cells to metastasize to distant sites via epithelial-mesenchymal transition (EMT) [143, 144]. Interplay between different stem cell signalling pathways also exists for EMT induction in cancers. AGE-RAGE interaction has regulatory role in the Wnt/β-catenin signalling pathway [Hallmarks of Cancer—Initiation to Invasion—RAGE/Ligands

Hanahan and Weinberg framed ten vital features of tumours as “hallmarks,” comprising of a multitude of biological characteristics adapted by cancer cells through the course of their genesis, progression, and metastasis [171]. It can be noted that RAGE, with its various ligands, is not just a mediator of inflammation or immune reaction. Given the right ligand touch, the receptor has an implication in each of the proposed hallmark of cancer, underlining its emergent role not only in different diseases but also in the different stages and features of cancer. Several hallmarks of cancers have been described and innumerable genes studied for deriving the rightful definition of tumours and curbing the underlying putative mechanism [171]. The downstream signalling cascade fuelled by sustained RAGE-ligand interaction in an inflammatory, hyperglycemic niche under constant oxidative stress, favours the derivation of different hallmarks of cancer (detailed in Fig. 3).

Fig. 3
figure 3

Molecular interplay between RAGE and its ligands directing the subsequent cellular events towards the execution of Hallmarks of Cancer. Each inner circle represents specific hallmark of cancer and the corresponding outer rectangular box depicts the genes or proteins involved in facilitating the particular hallmark upon RAGE stimulus

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Altogether, various signalling molecules concerned with RAGE-ligand interaction converge towards the promotion of an array of transcription factors NF-ķB, CREB, HIF-1α, STAT-3, and AP-1, instigating cancer survival, spread, stem cell renewal, and relapse. All the variant factors come together to uphold the metabolic and genomic dysregulation of tumours, favoured by unhindered rise in proliferative indices, molecular insults, and mutational load. A deeper understanding of the underlying molecular pathways points towards the inter-connection between RAGE-ligand signal network and neoplasms and targeting the same for successful onco-therapeutics.

Therapeutic Targeting of RAGE/Ligand Axis—the Epicentre of Genesis and Recurrence of Tumours

Throughout the various scientific approaches and developments made towards a cure of cancer, what makes the disease more challenging to treat and even more difficult to control is its ability to regrow and spread out branches simultaneously while trying to sever its roots with drugs. The process being explained by drug resistance and metastasis, which are the two most demanding aspects of cancer therapeutics, without which eliminating the mortality and morbidity of the disease would have been made possible with just the advent of cytotoxic drugs. The important fact is the aggression and rapidity with which cancers spread and metastasise to distant sites even after stringent chemotherapy and/or radiotherapy regimens. RAGE overexpressing tumours are found to be biologically aggressive with high malignant grade, poor prognosis, and higher inclination to metastasize and recur.

RAGE—Ligand—Cancer Cycle

Metabolic dependency of cancer cells is a major factor determining the aggressive nature of tumours. Tumour cells and/or niche exhibiting Warburg’s type of glycolytic dependency display elevated mitotic and metastatic indices [44]. High glycolytic rate of tumours favour invasion and metastasis through a vicious circle of cellular and molecular events (described in Fig. 4) characterised by hypoxia, hyperglycemia, glycation, and inflammation, involving RAGE directed signalling cascade. The RAGE signal cues lead to self-sustained cyclic events of oncogenic processes, responsible for the onset and propagation of cancers (detailed in “Cancer Metabolism and Glycation—AGEs” and “Glycolytic Dependency and Cancer Malignancy—AGEs and RAGE”). HIF-1α stimulated by intratumoral hypoxia leads to elevated glycolysis and lactate accumulation, by upregulation of proteins linked with glycolysis, cell growth, and glucose transport (“Metabolic Reprogramming and Sustained Growth Signals—AGEs” and “Invasion and Tumour-Associated Inflammation”). Lactate in turn activates Hyaluronan synthesis (dysregulated in cancers), instigates up regulation of HIF-1α, VEGF and enhances motility, creating the acidic micro milieu favouring angiogenesis and metastasis. Besides lactate upsurge, glycolysis and its glycating by-products perpetuate AGE generation, promoting HMGB1 and S100 proteins, evoking RAGE-NF-ķB and sustaining inflammation (explained in section “RAGE/Ligands—Glycation, Inflammation, and Hallmarks of Oncogenesis”). Downstream MAPK and PI3K/AKT pathways are activated mainly, further mounting up HIF-1α expression, thus fuelling the loop leading to tumorigenesis and promotion of cancers (section “Cancer Stem Cells and EMT”).

Fig. 4
figure 4

RAGE-ligand-Cancer cycle: Cellular cyclic events interlinking hypoxia, hyperglycemia, glycolysis, glycation, and inflammation from the origin of cancers to their invasion via RAGE-ligand-mediated molecular signalling axis

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Cancer can be initiated at any point in the cycle (Fig. 4), leading to an automatic ignition of non-stop tumorigenic events, advancing the tumour grade and aggressive nature, and evading further interference with oncotherapy, unless targeted with combinatorial therapeutics involving synergistic agents. Targeting RAGE and its ligands or MEK or mTOR inhibitors or any other individual targeted therapy alone as such can only serve to arrest the cycle temporarily. But again, it will trigger the vicious circle out of dormancy under favourable conditions, the point of origin being glycation or inflammation, which fuel the tumour in its nascent and resurrected states. Since all RAGE ligands also have RAGE-independent mechanisms of inducing cancers like Toll-like receptors for DAMPs and receptor independent tumorigenic effects of AGEs, this can finally lead to therapy resistance and tumour relapse. Hence, RAGE and its ligands have to be targeted simultaneously for better therapeutic inhibition, alongside conventional chemotherapy to ensure complete impediment of RAGE-ligand signalling mediated induction and propagation of cancers.

RAGE—Ligand-Targeted Therapeutics

We suggest simultaneous targeting of RAGE and its ligands in par with conventional chemotherapy regimen, which could aid in effective control and treatment of neoplasms. This requires the assimilation and assessment of inhibitors of RAGE and its ligands (small molecules, interfering RNAs, monoclonal antibodies, aptamers) studied so far in cancer and other RAGE related diseases and detailed notion of their possible implications in oncotherapeutics (Table 2) along with conventional measures. Utilisation of RAGE antagonists resulted in major blockade of tumour development and metastasis, as seen from various studies [73, 102, 202, 203]. Besides RAGE knockdown, abrogation of HMGB1 and S100 group of proteins has also shown inhibition of tumour growth and spread [89, 90, 110, 112, 204]. Direct RAGE antagonists like azeliragon and telmisartan have been assessed for their efficacy in Alzheimer’s (in phase III clinical trials) [205] and hypertension [206], respectively. Indirect RAGE antagonist, metformin blocks RAGE through its inhibitory activity on AGE-mediated disturbances in cell signalling [207]. These small molecule RAGE inhibitors mainly azeliragon and metformin can be exploited to understand their efficacy in cancer and advanced clinically to facilitate effective abrogation of RAGE and dependent oncogenic processes.

Table 2 Therapeutic targeting of RAGE and its ligands with implications in cancer treatment
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Anti-cancer drugs with RAGE binding affinity can have potential efficacy against cancers and one such drug has been proved to be cytotoxic against Endometrial and ovarian cancer cells (patent) [250]. Moreover, tamoxifen, a breast cancer drug has been found to enhance the endometrial expression of RAGE in breast cancer patients with or without endometrial cancer. This could possibly imply tamoxifen as an inducing factor of endometrial cancer in breast cancer patients and promotion of metastasis in patients already with endometrial cancer. As reported, instigation of RAGE expression by tamoxifen can be mitigated by combining it with an anti-cancer drug, capable of binding and inhibiting RAGE. Methotrexate has been reported to hinder HMGB1 and RAGE interaction by binding HMGB1 in RAGE binding site and down regulate the interaction dependent mitogenic and inflammatory activities [181]. Cytotoxic drugs with similar antagonism against RAGE and/or its ligands can be analysed for plausible implications in effective oncotherapy. Plant derived drugs like curcumin [208], quercetin [194], epigallocatechin gallate [210], quercetin [195], resveratrol [211,212,213], genistein [214, 215], and garcinol [216, 217] have been found to possess both anti-cancer and anti-glycation activities (AGE inhibitors), which could be utilised in the context of AGE targeting in cancer treatment. Of these, resveratrol has been shown to inhibit both AGEs and RAGE in diabetes and effective in cancer management. Several small molecules, aptamers, antibodies, peptibodies, interfering RNAs, capable of inhibiting RAGE and/or its ligands—AGEs, HMGB1, and S100 that have been proved to be effective in cancer through several in vitro and in vivo studies are detailed (Table 2) for plausible translation of their application in clinical oncotherapeutics. In an ongoing clinical trial conducted in Medical University of South Carolina (2017–19), Carolyn Britten and colleagues have attempted to evaluate the effect of metformin and a derivative of grape seed extract on the level of AGEs in metastatic breast cancer and prostate cancer patients to establish the possible relationship between AGEs and cancer and assess the AGEs inhibiting potential of the drugs for implications in cancer treatment (clinical trials) [251, 252]. We studied a novel pharmaceutical formulation of phytopolyphenols—a flavonoid glycoside, diosmin, and a naphthoquinone, plumbagin in MDA-MB-231 cells (TNBC). We obtained promising cytotoxic effects revealing potent synergistic anti-proliferative efficacy of the polyphenols with greater than 80% inhibition, combination index as low as 0.3, even at minimal doses. The combination involved the use of Diosmin displaying anti-glycation activity, for the potentiation of anti-cancer effects of the formulation. We observed enhanced cytotoxic efficacy of the formulation rather than individual drugs, with efficient dose reduction index (DRI > 1) upon inclusion of an anti-glycation agent or AGE inhibitor (diosmin) for the first time (patent) [248]. This formulation unravelled the potent anti-neoplastic efficacy of the drugs targeting glycation/glycoxidation in cancer. The chemo-preventive and ROS scavenging effects of the specified anti-glycation agent might serve to prevent and delay cancer incidence, considering the age, AGEs, and ROS-related degenerative changes and genomic insults to the body, contributing to cancers in the aged and risk population.

Certain antibodies, peptibodies, anti-inflammatory, anti-histamine, anti-protozoal, and quinolone derivatives have been found to be antagonists of different S100 group of proteins (Table 2). S100 group of proteins and AGEs exhibit different types of proteins (S100 A4, S100B, S100P, etc.) and structural diversity (different AGEs depending on glycating agent and glycated molecule), using antibodies against single protein may not target all the isoforms, unlike RAGE and HMGB1. Hence, small molecule inhibitors of AGE formation and general S100 inhibitors could provide a wider coverage for the designated drugs. Although S100 inhibitors have been identified, the long half-life of S100 proteins interferes with attaining the constant and sufficient low levels of protein required to produce the drug effects [87].

Inhibitors of protein translocation across biological membranes have also been suggested as possible novel anti-cancer drugs [218]. AGEs, HMGB1, and S100 proteins formed intracellularly can be secreted into the extracellular space upon stimulation [83, 166, 219], and in turn trigger RAGE, inducing strong upregulation of RAGE downstream pathways. Hence, we state that protein translocation blockers can be utilised for preventing the extracellular release of internal RAGE ligands and further RAGE instigation, in addition to the blockade of extracellular RAGE and its ligands by targeted therapeutics.

Potential Advantages of RAGE—Ligand-Targeted Therapeutics

Adding together all the factors, we have listed the possible advantages of involving RAGE-ligand targeted therapeutics in cancer treatment for achieving better prognosis, effective cancer control, and curbing tumour recurrence.

  • Taking into account the pleiotropic behaviour of AGEs in cancer from initiation to invasion, AGE inhibitors, or anti-glycation agents (via control of glycoxidative damage and genomic insults) can have potential applications in cancer from prevention of its occurrence to the prevention of metastasis and cancer recurrence. RAGE-ligand targeted therapy can be coupled with conventional chemotherapy and/or anti-glycation and anti-inflammatory agents, mainly anti-glycation agents like diosmin, quercetin, resveratrol, genistein, and garcinol meant to control overall cellular events besides the molecular components assisting oncogenic processes.

  • Molecular chaperones can be used along with targeted or conventional chemotherapy, since glycation and mutations result in improperly folded proteins forming aggregates, which encourage strong binding of RAGE by its oligomerization and hence RAGE stimulation; several dysregulated proteins in cancer are targets of HSP-90, a molecular chaperone, known to be mutated and downregulated in many cancers [220].

  • Cytotoxic agents with anti-oxidant activity or administering anti-oxidants following conventional chemotherapy could serve to impede the development of resistance to chemotherapy, by mitigating oxidative stress, which otherwise could by themselves evoke AGE generation, angiogenesis (VEGFR activation by ROS), additional genomic and proteomic damage, evasion of apoptosis, and therapy resistance. Since individual anti-oxidant agents have the paradoxical action of promoting cancer, cytotoxic drugs with inherent anti-oxidant potential such as certain flavonoids can be combined for prevention of drug resistance.

  • Evaluation and development of Receptor (RAGE)/ligand (S100/HMGB1) targeted new cytotoxic lead molecules for effective control of origin, spread, relapse, and drug resistance of tumours. The inflammatory (HMGB1) and ROS molecules released from dying cancer cells following chemo/radiotherapy trigger cancer relapse by promotion of downstream oncogenic signalling via RAGE, TLR, and TGF-β [86]. Therapy resistance elicited by HMGB1 and ROS can be prevented using HMGB1 inhibitors and/or ROS scavengers (anti-oxidants) together with cytotoxic drugs.

  • Cancer associated fibroblasts also express AGEs, HMGB1, and S100 group of proteins, activating RAGE in cancer cells. Combination therapies involving antagonists to RAGE, AGEs, HMGB1, and S100 proteins, along with conventional treatment measures for cancer can provide multi-targeting of cancers with varied genomic signature, minimising drug resistance, tumour recurrence, and improving patient survival. Small molecule inhibitors like curcumin and quercetin, acting against AGEs, RAGE, and HMGB1 can be exploited for their pleiotropic therapeutic effects in synergism with cancer chemotherapy.

  • Targeting RAGE and its ligands offers selective toxicity to the developed anti-neoplastic drugs, thus preventing undesirable side effects to normal cells, as they are expressed in high amounts only under pathological conditions, whereas non-cancerous, homeostatic cellular environment express RAGE and its ligands negligibly; additionally, RAGE over expressing precancerous lesions, tumour stroma, and tumour adjacent normal tissues which originate, fuel, and regenerate cancer, respectively, also can be eradicated.

  • Since RAGE is highly expressed in almost all cancer types and there is a proportionate increase in malignant nature of tumours with its elevated levels, develo** an anti-cancer drug target against RAGE can aid in treating different types of cancers, especially those with high metastatic grade like TNBCs, which lack recognised target receptors; thus serve to control aggressive cancers with poor prognosis.

  • Ageing leads to degenerative cellular changes by glycoxidative stress (as AGEs also increase with age) and accumulating mutations by sustained genomic damage, accompanied by weakened immune system, which are the major factors cumulative towards the predisposition of aged/older population to cancer incidence. Highlighting the application of anti-glycation (AGE inhibitors) and anti-oxidant agents as chemo-preventive therapeutics could serve towards healthy ageing, free from fatal malignancies, and increased overall and disease-free survival even after incidence, by curbing the cellular and molecular damages caused by pathological factors as diabetes, obesity, genetic predisposition (BRCA1 etc.,), and physiological factors as ageing. Chemo-preventive approach to cancer susceptibles like diabetics and BRCA1 mutation carriers, as in the case of familial breast or ovarian cancers, could be made possible by administering (preferably plant based) anti-glycation agents even before the onset of cancer (Since AGEs have been reported to up regulate estrogen receptor, besides RAGE, making a diabetic more prone to breast cancer).

  • Immunotherapy is gaining momentum in recent cancer research and targeting RAGE-ligand duo can provide effective immunotherapeutics (since antagonists of downstream targets of RAGE such as CTLA-4 and MDSC are assessed for evoking immune activation), working to unhinge the tumour immune evasion mechanics.

Thus, RAGE and its ligands, AGEs, HMGB1, and S100 group of proteins (S100A4, S100P, S100B, S100A8, and S100A9) serve as potential therapeutic targets for cancer.

RAGE-Ligands and Cancer Diagnostics

Recent discoveries of certain onco-suppressive agents have been found to limit progression of the disease, but are found efficient mainly if diagnosed at the early stages of cancer. Many cancer screening techniques have been adopted for prevention, early detection and effective treatment of the disease, while the tumour is still in budding stage. But the silent, asymptomatic nature of most cancers in their initial and even late stages makes it difficult to diagnose or they remain undetectable until too late to treat. This necessitates the advent of newer biochemical and molecular diagnostics, capable of detecting even small masses of malignant tumours at an early stage with precision and accuracy, specific enough not to pick non-malignant tumours as cancers and sensitive enough not to mistake malignant growths as non-cancerous ones. Hence, we have analysed RAGE and certain RAGE associated components for their efficacy as diagnostic and prognostic biomarkers in different cancers.

RAGE Gene Polymorphism—Cancer Biomarker

Certain polymorphisms of RAGE are associated with cancer risk and disease prognosis, mainly, oral, breast, lung, gastric, hepatocellular, colorectal, and pancreatic cancers (Table 3). Of the 30 polymorphisms reported in RAGE gene, Gly82Ser polymorphism is studied more owing to its location in ligand binding V domain of RAGE. This glycine to serine change at position 82 promotes glycosylation, enhancing the RAGE ligand binding, its activation, thus altering its functions and making the carriers prone to certain cancers, diabetes [234] and inflammation [235].

Table 3 Functional implications of RAGE gene polymorphisms in cancer
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This G82S polymorphism is related with sensitivity to cancer treatment for thermotherapy in non-small cell lung cancer (NSCLC) [223]. G82S and -374T/SA are most commonly seen RAGE variants with significant impact in cancer risk and invasion. Interplay between specific RAGE gene polymorphisms and environmental mutagens is observed to be a predisposing factor for oral cancer [227]. Besides their role in cancer risk and affecting treatment response, a few genotypic variants of RAGE are also associated with eliciting metastasis [221, 225, 227].Thereby further screening for RAGE gene polymorphisms in cancer patients could serve to predict the cancer risk, early onset, prognosis, tendency to metastasise and response of tumours to different therapies.

While certain gene polymorphisms as rs2070600 (G82S) and rs1800624 (-374T/A) are suggested as potential screening/diagnostic markers and futuristic therapeutic targets [229], the same polymorphism (-374T/A) which decreases the cancer risk in Caucasians [228], is observed to increase the cancer risk in Asians [230]. And the same polymorphism (-374T/A) which confers reduced risk against one cancer (breast cancer), increase the risk for another cancer (lung cancer) [229]. All these observations imply that RAGE gene polymorphisms could be used as genetic markers to diagnose the risk subjects at an early stage. Major challenges of cancer treatment being metastasis and recurrence, screening for most common genotypic variants associated with cancer invasion like G82S, could help assess the metastatic inclination of cancers to enable early drug targeting.

Plasma Soluble RAGE—Cancer Biomarker

sRAGE (soluble RAGE) said to be one of the splice variants of RAGE, lacking trans membrane and cytoplasmic domain; nullifies the actions of RAGE by competitive ligand binding [236]. sRAGE exist in circulation in normally higher levels and supposedly neutralises the RAGE functions. Hence, the increased or decreased levels of sRAGE protect from or make a person prone to cancers and certain age related disorders [237]. Studies report the decreased sRAGE levels in cancer patients compared to the healthy controls and lower sRAGE levels are found to be associated with increased cancer risk [238, 239]. sRAGE levels are inversely correlated with tumour stage and positively correlated with patient prognosis [236, 240,241,242]. Reduced sRAGE levels are related to progression of breast, lung, liver and colorectal cancers. Hence circulating sRAGE could be used as diagnostic and prognostic biomarker for cancer, besides serving as a decoy molecule or defence mechanism in the prevention of RAGE related pathologies like Alzheimer’s, diabetes and cancer.

As seen from several studies, carriers of certain RAGE polymorphism (Table 3) are prone to have lesser plasma soluble RAGE forms, hence making them susceptible to certain cancers. Different RAGE genotypic variants of G82S have been associated with either reduced or elevated plasma sRAGE levels [232, 233, 243]. Further, correlating the plasma levels of sRAGE with existing RAGE genotypic variants of the subject could reveal the cancer risk in unaffected groups and serve to predict therapy response as well as monitor disease prognosis in cancer individuals. Furthermore detailed analysis for different polymorphisms and plasma soluble RAGE forms in various populations and several cancers would warrant in-depth outlook into the application of these polymorphisms in cancer diagnostics and targeted therapeutics.

Tissue RAGE—Cancer Biomarker

RAGE is a significant diagnostic biomarker, considerably elevated in advanced-stage and highly invasive cancers; an important predictor of tumour stage, progression and recurrence in several cancers including oral and breast carcinoma [45, 244]. We have tried to evaluate the significance of RAGE as a biomarker both in non-cancer and cancer subjects.

  • Metastasis and recurrence tend to be the point of failure of most anti-cancer drugs, decreasing the survival rate of cancer patients. Through evaluation of RAGE and its ligands expression in tumour tissues, we can predict the propensity towards metastasis and recurrence in proportionate with its expression, assess the severity of the disease and treat patients with RAGE-ligand specific antagonists. For cancer survivors or those in remission, constant monitoring for RAGE expression, sRAGE levels and AGEs could help monitor the onset of secondary cancers or cancer relapse.

  • Significant RAGE overexpression in cancer tissues compared to normal adjacent tissues, indicates the diagnostic role of RAGE in cancers. RAGE expression has been reported to increase parallel with the histological grade, tumour size, stage (nodal and metastatic status, AJCC stage), invasive depth and local recurrence [46]. Substantial augmentation of RAGE expression has been observed in aggressive, advanced-stage, metastatic tumours and node-positive tissues compared with other tissues [45]. Hence RAGE-ligand antagonists could serve to treat not only primary but also the undiagnosed metastatic cancers, preventing recurrence [29, 47].

  • The multi-characteristic features of RAGE incorporates its role in different stages and hallmarks of cancer; entails it as a significant biomarker for diagnosis and prognosis of cancers. Highly elevated RAGE expression is a diagnostic as well as a prognostic biomarker to monitor the efficacy of chemotherapy in controlling tumour growth and spread. Upregulated RAGE expression especially in the invasive cancer front implies its prominent role in metastasis and blockade of the same for prevention of metastasis and further disease progression [244].

  • Subdivision within tumour stages can be made based on the expression levels of RAGE in tumour tissues. Late stage cancers without RAGE over expression is possibly indicative of less propensity towards metastasis, local recurrence and better patient survival. Whereas with high RAGE expression in late stages, possibly imply the requirement of (RAGE-ligand) targeted agents and intensive chemotherapy for curbing metastasis, relapse and improving patient survival. High RAGE expression in stage 3 and 4 cancers have revealed overall poor patient survival [245]. When using RAGE blockers, the effectiveness of the treatment and prognosis of the disease can be scrutinised by screening for RAGE expression levels before and after the treatment.

Hence, we propose RAGE could be an efficient diagnostic and independent prognostic biomarker for cancers.

Serum and Tissue AGEs—Cancer Biomarker

  • Upregulation of AGEs in normal tissues surrounding tumours (mentioned in “RAGE-Dependent Effects of AGEs”) suggests the involvement of AGEs in cancer genesis via the stimulation of RAGE expression later leading to tumour progression.

  • Accumulation of AGEs and subsequent RAGE signalling increase cancer risk [9]. Circulating AGE modified protein (argpyrimidine and CML) and DNA (CEdG) can be elucidated as biomarkers for early screening and detection of cancers.

  • Glycated adducts of bio macromolecules in circulation can also be estimated for potential carcinogenic injury to the body system in susceptible individuals, such as those exposed to harmful radiation and chemical carcinogens.

  • Autoantibodies to glycated conjugates of biomolecules can act as valid estimates of glycoxidative damage and possible indicators of abnormal cell metabolism during silent oncogenesis.

  • In people susceptible to cancer such as BRCA1 mutation carriers and people with diabetes, constant screening for greater than normal elevated levels of CEdG, argpyrimidine, CML, and S100 proteins in circulation may reveal the cancer in the early stages.

  • Autofluorescent property of AGEs (Argpyrimidine) can be made use of by checking for their accumulation in mammary glands as a routine health check-up, e.g. mammogram, every year to rule out breast cancer; similarly auto fluorescence technique can be used for assessing skin cancer (melanoma), which can be a non-invasive method compared to screening blood for biomarkers.

  • Other non-invasive methods of measuring AGEs include screening tears, saliva, and urine of patients for prognostic significance, by spectrofluorimetry and ELISA techniques.

  • S100 proteins, mainly S100P, S100A8, and S100A9 are significant diagnostic and prognostic biomarkers of breast cancer, urothelial, hepatocellular, renal, colon, and other cancers [177, 178, 246, 247]. Hence, screening for S100 proteins could help in prompt diagnosis of cancers and prognosis of cancers and to evaluate the tumour stage and drug responsiveness.

RAGE Polymorphism, sRAGE, RAGE, and AGEs—the (S)quad of Cancer Biomarkers

The expression of RAGE and AGEs is proportionate with the malignant and metastatic grade of cancers. Additionally, sRAGE levels and RAGE polymorphisms indicate the susceptibility of a person to specific cancers. The increasing sRAGE levels with RAGE targeted/conventional chemotherapy indicate better prognosis.

Hence in progressed cancers and at any cancer stage, screening for the levels of serum AGEs, plasma soluble RAGE, RAGE in tumour tissues, and existing RAGE gene polymorphisms (82G/S, -374T/A) can help to assess the degree of severity of the cancer, its propensity towards metastasis and the patient’s responsiveness to treatment.

Altogether, the four key components associated with RAGE namely, RAGE polymorphisms, sRAGE, AGEs, and tissue RAGE, can be effectively exploited as novel diagnostic and prognostic biomarkers in cancer. Investigating and correlating the factors of “four” in both cancer and non-cancer subjects can have prospective implications, explained as follows:

  • To predict the predisposition to cancer incidence

  • To diagnose cancers at an early stage

  • To monitor the prognosis of primary cancers

  • To evaluate the efficacy of different oncotherapeutic agents

  • To predict the propensity towards metastasis and recurrence

  • To prevent the secondary or metastatic cancers

  • To treat the undiagnosed metastatic cancers alongside primary cancers

  • To assess the overall and disease-free patient survival

  • To evaluate the need for use of RAGE-ligand targeted therapy, alongside conventional therapies for cancer.

It is notable that except RAGE gene polymorphism, all the other three can be altered with specific drug treatments or measures; such as AGEs with anti-glycation agents or AGE-inhibitors, plasma sRAGE, and tumour RAGE with RAGE-targeted therapeutic agents. Hence, screening for this RAGE (s)quad of biomarkers could enable preventing the cancer incidence and progression to metastasis and relapse, at early stages with targeted treatment. We have added together the existing and novel upsides of exploiting RAGE-ligand antagonists and RAGE (s)quad of therapeutic targets for controlling the onset and expansion of cancers.

Conclusion

Develo** RAGE-ligand targeted therapeutics and diagnostics can serve to treat and diagnose cancers in a better way. Combining cancer chemotherapy with inhibitors of RAGE, AGEs, and other RAGE ligands could provide multi-dimensional approach for curbing tumours with varied genomic architecture, since abnormal growths do not always have a uniform genomic profile. RAGE-ligand signalling network plays significant role in each of the hallmark of cancer, commencing from origin to spread (Figs. 1–3). RAGE-ligand antagonists could significantly target the Achilles heel of cancers mainly, poor prognosis, silent metastasis, drug resistance, and cancer recurrence, since blockade of RAGE or HMGB1 or S100 proteins alone have exhibited considerable reduction in tumour size, invasion and angiogenesis of several cancers [73, 89] (Table 2). Of all, overall and disease-free survival of cancer patients can be extended to confer them with better quality of life, while simultaneously trying to mitigate the morbidity and mortality. Although various mechanisms have been coined, timely detection and treatment of cancers still remain elusive and the field remains still as ongoing research. Proper utilisation of the (s)quad of RAGE-ligands and RAGE-biomarkers for appropriate sorting of neoplasms from normal cells at the budding stage could make cancers more curable and controllable. Deeper knowledge of the neoplastic molecular mechanisms so derived needs to go hand in hand with translational implications for patient benefits. Transforming book information to a laboratory test tube and deciphering the same for a live tumour milieu requires the convergence of different expertise towards the expansion of targeted and combinatorial therapies and liable screening techniques for improved detection and management of cancers in future. In this review, we have attempted to give a prelude to the same.