v
Search
Advanced Search

Publications > Journals > Cancer Screening and Prevention > Article Full Text

  • OPEN ACCESS

The Positive Feedback Loop Between Inflammation and Mutant KRAS Genes Promotes Malignant Transformation in Chronic Pancreatitis

  • Fan Yang1,#,
  • Lei Li2,# and
  • Xiang-Yu Kong1,* 
 Author information
Cancer Screening and Prevention   2022;1(1):39-46

doi: 10.14218/CSP.2022.00012

Abstract

Pancreatic cancer (PC) is one of the most dismal diseases with a five-year survival rate of only 6%. Such poor prognosis is attributed to both a lack of early detection methods and its intrinsic resistance to cytotoxic agents and radiotherapy. Identifying driving events in the initial stage is of great significance for curable pancreatic ductal adenocarcinoma (PDA) detection and effective targeted therapy. Furthermore, Kirsten rat sarcoma viral oncogene (KRAS) plays a critical role in the initiation and maintenance of pancreatic tumors, thus contributing to the conversion of anti-tumor inflammation to pro-tumor inflammation. Both the KRAS mutation and inflammation are concurrent in the initial stage of PDA, and they compose a positive feedback loop to enhance each other’s activity. This positive feedback loop generates a harsh environment, which helps pancreatic cells maintain the stemness phenotype, accelerates cell turnover rate, increases genome instability, and hence elevates the incidence of PDA formation.

Keywords

Pancreatic cancer, KRAS, Inflammation, Chronic pancreatitis

Introduction

Pancreatic cancer (PC) is one of the most malignant types of tumors and is the seventh leading cause of cancer-related deaths worldwide.1 Moreover, pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of all pancreatic cancer cases. In contrast to the steady increase in survival for most cancers, advances have been slow for PC, for which the overall five-year relative survival is currently 6% (2–9%).2 The low survival rate is partly because more than half of the cases are diagnosed at an advanced stage. Patients with limited lesions of the pancreas have a five-year survival rate of 29.3%, yet the rate for advanced patients is only 2.6%.2 Hence, an effective screening method for its early detection is still lacking. Furthermore, the modified chemoradiation treatments have a limited impact on the course of disease despite some advances.3,4

It has been well established that pancreatic carcinogenesis undergoes an extremely long course during which numerous genetic events accumulate within the pancreatic cells with a stemness phenotype. A list of environmental factors has also been identified to predispose an individual to pancreatic cancer, including smoking, alcohol consumption, chronic inflammation, etc. Compared with the first two factors which only confer a low risk (relative risk ≈2),5,6 chronic inflammation shows a stronger association with PDA with its increased risk ranging from 3.53 to 16.16.7 Molecular pathology has shown that most PDA cases begin in the context of inflammation, and are derived from acinar cells.8 Communication between the acinar cells and the inflammatory milieu converts them into ductal-like cells, then progresses into a pancreatic intraepithelial neoplasia sequence, and finally ends up with PDA.8 Accredited reports support that inflammation could accelerate accumulations of genetic events within pancreatic cells, and sequentially accelerate the process of pancreatic carcinogenesis. However, though several genes and molecular pathways have been validated to be involved in this process, targeted therapy against these genes have shown little efficacy in the clinic. As a consequence, identification and validation of causative genes and molecular pathways underlying PDA progression are critical for the rational development of effective strategies for diagnosis and intervention.4,9

Identifying and dissecting driving events in the initial stages of PDA is critically important for PDA research

Based on the clonal relationship between a primary tumor and metastasis, a previous study indicated that this needed an average of 11.7 years to transform the initiating mutation into the parental, non-metastatic founder cell, and an average of 6.8 years was required for the acquisition of the metastatic ability; nevertheless, the patients died on average two years thereafter. These data defined a broad time window of opportunity for early detection to prevent deaths from metastatic disease.10 However, most PDA cases were diagnosed at an advanced stage (Fig. 1) with a five-year survival rate of less than 3%. In addition, targeted therapy in these patients showed only marginal effects. Furthermore, recent studies have stressed the importance of studying the genetic and immune microenvironmental alterations occurring in the early stages. Therefore, the identification of genes and immune pathways involved in early-stage PDA formation would not only enable us to develop novel early detection strategies, but also help to better understand the primary causal factors for PDA and thus provide potential targets for new therapeutic modalities.

Natural course for the development of PDA.
Fig. 1  Natural course for the development of PDA.

It takes decades to fully develop into a PDA. However, most PDA cases are diagnosed at an advanced stage (time after the yellow dashed line). The targeted therapy against these patients showed marginal effects. Recent studies stressed the importance of studying the genetic alterations that had occurred in early stages. PDA, pancreatic ductal adenocarcinoma.

Chronic inflammation is a hallmark characteristic for PDA

Chronic inflammation is critically important in PDA carcinogenesis

The possible links between inflammation and PDA could be readily deduced from the widespread presence of inflammatory cells in the PDA mass. As such, now clear evidence has been obtained that inflammation plays a critical role in pancreatic tumorigenesis. Moreover, epidemiological studies have shown that chronic inflammation could significantly elevate the incidence of PDA,7,11 and in hereditary pancreatitis, which begins at a young age (about 10 years old), the cumulative rate of pancreatic cancer diagnosis could reach 22.8% at 70 years.12 Therefore, genetic mouse models helped us clearly define the critical role that inflammation plays in PDA tumorigenesis. For example, chronic pancreatitis could induce acinar-to-ductal metaplasia (ADM), which has been well established as an important precancerous lesion during PDA formation. Likewise, acinar cells and insulin-expressing endocrine cells in adult mice become refractory to K-RAS2V-induced PanIN and PDA unless they are exposed to chronic pancreatitis.13,14 The vast majority (90%) of PDA are linked to somatic mutations and environmental factors.15 Many environmental risk factors, including tobacco smoke,16 obesity,17 and even old age,18 exert an array of pro-tumorigenic signals through inflammatory mechanisms. In certain cases, inflammation could diminish the beneficial effects of the therapy.19 Additionally, the incidence and mortality of many cancers are reduced when using non-steroidal anti-inflammatory drugs, such as aspirin on nonspecifically suppressed inflammation.20,21 Regular aspirin use has been associated with a reduced pancreatic cancer risk among participants with diabetes.22 Thus, all this evidence supports the critical role that inflammation plays in PDA.

Possible mechanisms involved in chronic inflammation to cancer progression

Several lines of evidence support the roles that inflammation plays in carcinogenesis. Firstly, inflammation could induce the production of cellular mutations, directly or indirectly. At the sites of inflammation and infections, activated inflammatory cells like macrophages and neutrophils could generate reactive molecules into the microenvironment, e.g., reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI). All these molecules would be cytotoxic and capable of inducing DNA damage and genomic instability in the pancreatic cells.23 Chronic inflammation triggering tissue damage could also weaken the barrier function and expose the stem cell compartment to environmental carcinogens or bring stem cells to a close proximity of active inflammatory cells producing genotoxic compounds (Fig. 2).19 Secondly, inflammation could accelerate mutation accumulation in the pancreatic cells. Genome instability is the critical characteristic of the cancer cells enabling other hallmarks in cancer development. In normal cells, the genome maintenance systems could detect and resolve the defects in the DNA and ensure the rates of spontaneous mutations would be extremely low during each cell generation.24 In the setting of chronic inflammation, the cell turnover rate would be greatly accelerated, which would confer increased susceptibility to DNA damage. Thirdly, as PDA is an aged disease and it would take more than one decade to form a PDA, sequentially occurred somatic mutations would accumulate within a subset of long-lived stem cells with a self-renewal property.25 Many downstream effectors of inflammation, such as nuclear factor-κB (NF-kB)26,27 and signal transducer and activator of transcription 3 (STAT3),28 are closely associated with a self-renewal phenotype of the stem cells, which would protect them from being eliminated before the next mutation acts. Last but not least, inflammation could help sustain the malignancy of the transformed cells by supplying bioactive molecules to the microenvironment, including growth factors that would sustain proliferative signaling, survival factors that limit cell death, invasion, and inductive signals that would lead to the activation of epithelial-mesenchymal transition (EMT) and other hallmark-facilitating programs.29,30 These signaling factors would act on a mutational basis to promote further transformation of precancerous lesions to cancer, metastasis, and the spread of cancer. It has been shown that in order for the early pancreatic intraepithelial neoplasia (PanIN) lesions to develop to PDA in Kirsten rat sarcoma viral oncogene (KRAS) mutated mice, activation of the STAT3 pathway by interleukin 6 (IL6) would be required.31 A study showed that the ablation of the IkappaB kinase β (IKKβ) led to a reduction in tumor growth in a model of colitis-associated cancer.32 Preoperative stimulation of the resolution of inflammation or inflammation blockade responses resulted in poor colonization and eradicated the micro-metastases.33

Inflammation could induce the production of cellular mutations, directly or indirectly.
Fig. 2  Inflammation could induce the production of cellular mutations, directly or indirectly.

Activated inflammatory cells could generate DNA damage factors, such as reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) into the microenvironment. Furthermore, chronic inflammation triggering tissue damage could weaken the barrier function and expose the stem cell compartment to environmental carcinogens or bring stem cells to a close proximity of active inflammatory cells producing genotoxic compounds. RNI, reactive nitrogen intermediates; ROS, reactive oxygen species.

Inflammation alone is not sufficient to induce PDA formation

A study of mouse models of chronic inflammation of the pancreas found that mice lacking tumor protein P53 (TP53) developed pancreatic cancer, while TP53 wild-type mice did not, thus suggesting that inflammation alone was not sufficient to cause pancreatic cancer.34 As previously mentioned, the development of pancreatic cancer would require a long course, in which multiple sequential steps would result in the accumulation of multiple random “hits” to the pancreatic cell DNA from specific types of environmental factors, e.g., inflammation. One strong evidence for this concept comes from hereditary pancreatitis (HP), an autosomal dominant genetic disorder with long-lasting pancreatitis. Although pancreatic inflammation in HP begins at a median age of 10 years, the marked increase in the incidence of PDA does not occur until the sixth decade of life.12,35 Furthermore, the risk for PDA does not correlate with the severity of the inflammation and fibrosis. As a consequence, all these observations would suggest that the high risk for PDA in the general population would represent a combination of existing pathogenic cancer gene variants plus environmental factors, whereas inflammation itself would only act as a promoter, but not a cell fate determinant in PDA formation.36

Another important reason for the inflammation’s insufficiency in inducing PDA would come from the theory that the ever-alert immune system could constantly monitor the cells and tissues. In normal cells, the anti-tumorigenic function of immunity would exert immunosurveillance and immunological sculpting of tumor heterogeneity. Such immune surveillance could recognize and eliminate the vast majority of incipient cancer cells and thus nascent tumors. Studies have also shown that people with a personal history of allergies have been known to have a protective effect against pancreatic cancer. Individuals with allergies have a decreased risk of cancer and an increased survival rate compared to those without allergies.37 This could explain why striking increases of certain cancers occur in immunocompromised individuals.38,39 However, with the accumulation of the mutation in the tumor microenvironment (TME), cell death and microbial signals would altogether feed into a feed-forward loop of inflammation-induced signaling and inflammatory cell recruitment. Hence, the sterilizing immunity would not remove the mutation, thus resulting in cancer-promoting inflammation.19 Such immune escape is a hallmark of all cancer types, and cancer cells must well evade immune destruction by disabling the components of the immune system that have been dispatched to eliminate them, so to grow successfully into a solid tumor mass.24,40 These two immune models existing in different microenvironments would also confirm that inflammation alone would not be sufficient to induce PDA formation.

KRAS mutation is critically important for PDA initiation

KRAS mutation is the initial and ubiquitous event in pancreatic carcinogenesis

Genome instability and associated genetic diversity are the key characteristics of tumors underlying those so-called “hallmarks of cancer”.24 Substantial efforts have been devoted to determine the genetic mutations of PDA, and hundreds of changes of gene expression have been identified compared with normal pancreatic cells.41 Though a small group (2–10%) of PDAs seem to be associated with hereditary factors, most are associated with high-frequency somatic mutations in a subset of genes, including KRAS, cyclin-dependent kinase inhibitor 2A (CDKN2A), TP53, and SMA- and MAD-related protein 4 (SMAD4).42 Of note, KRAS mutation is nearly universal (>95%) in human PDA. Furthermore, PDA is associated with non-invasive, preneoplastic lesions that are thought to be precursors to the disease. PanIN is the most common and most widely studied putative precursor. A sequential transformation model, from PanIN-1, PanIN-2, PanIN-3, until PDA, has been well established for PDA, and numerous genetic alterations have also been documented in different stages. In PanIN-1, mutated KRAS was frequently detected (estimated to be over 36%43,44), whereas the other PDA associated mutations, e.g., TP53 or SMAD4, remained intact. Owing to its near universal frequency in PDA, the mutation of KRAS was proposed as the initiating genetic lesion in PDA. Genetic models holding constitutively active KRAS helped us dissect the key role that mutant KRAS plays in PDA progression.

Genetic models developed in the context of oncogenic KRAS provide important tools in PDA studies

Hingorani et al. first developed the conditional KRAS-driven PDA mouse model that recapitulated the progression observed in humans.45 From then on, almost all PDA genetic models were generated on the basis of cre-mediated KRAS mutation, e.g., KC (Pdx1-Cre; LSL-KRASG12D or Ptf1a-Cre; LSL-KRASG12D) and KPC (most commonly Pdx1-Cre; LSLKRASG12D; LSL-Trp53R172H or Ptf1a-Cre; LSL-KRASG12D; LSLTrp53R172H) mouse models. Employing these models, researchers explored the origination of PDA by cell lineage tracing, dissected unraveled mechanisms by crossbreeding with other genetic mutation models, and evaluated the therapeutic efficacy of certain anti-cancer agents to PDAs. Neither the presence of inflammation, nor the loss of tumor suppressor genes would be sufficient to initiate PDA in the absence of oncogenic KRAS, which would highlight the unique role that KRAS would play in the onset of PDA.46

KRAS plays a central role in the initiation and maintenance of PDA by activating downstream effector pathways

Activated KRAS mutants initiate numerous signaling pathways. All of these pathways contribute to the oncogenic and proliferative power of KRAS, including the mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-Kinase (PI3K) pathway, Ras-like (RAL)A–RALB pathway, the p38 mitogen-activated protein kinases (p38-MAPKs) pathway, Jun N-terminal kinase (JNK) pathway, and NF-κB pathway. MAPK signaling promotes the formation of PanINs by enabling the dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.47 Activation of the PI3K family would lead to the activation of phosphatidyl inositol triphosphate and to the downstream activation of the Ak strain transforming (AKT) and mammalian target of rapamycin (mTOR) molecules. This pathway has been shown to be upregulated in PDA.48 In pancreatic cancer, RALA promotes tumor initiation, whereas RALB is essential for invasion and metastasis.49 The p38-MAPKs pathway promotes invasive abilities of pancreatic tumors,50 while the JNK pathway promotes pancreatic tumor formation and cancer stem cell maintenance.51 The NF-κB pathway modulates pancreatic cancer cell malignancy and tumor growth through cell cycle signaling.52 In addition to these classic pathways, many other proteins containing putative KRAS- association or KRAS-binding domains have been described, including the SARC, STAT3, cyclooxygenase-2 (COX2), and early growth response 1 (EGR1) pathways.53

Oncogenic KRAS alone might not be sufficient to transform a cell

Though KRAS is indispensable for PDA formation, numerous studies have reported that healthy humans carry oncogenic KRAS in different organs, including the pancreas,54 colon,55 and lungs,56 at rates far exceeding the rates of cancer development.46 Furthermore, mice that express oncogenic KRAS, either in the whole body or in specific organs, develop cancers from only a small fraction of the cells that contain the oncogenic KRAS.57,58 Mouse models showed that the oncogenic KRAS remained locked in an “Off” state but could be readily activated by upstream stimulants to lead to prolonged strong Ras activity.59 Consequently, a threshold level of KRAS activity might be essential to initiate the carcinogenesis process.60,61 Therefore, these results indicated that oncogenic KRAS alone was not sufficient to transform a cell, and other genetic/epigenetic factors would be required to elevate the activity level of mutant KRAS to initiate carcinogenesis.

KRAS-inflammation feed-forward loop plays important roles in PDA initiation

Oncogenic KRAS could regulate the inflammatory environment of PDA

A list of inflammatory signals has been validated to be downstream effectors of KRAS,62 e.g., COX-2, STAT3, and NF-κB, which have indicated that oncogenic KRAS itself is closely associated with inflammatory pathways. During the earliest stage of the PanIN formation, the lesions would accumulate proliferating cells of mesenchymal origin that might comprise fibroblasts and pancreatic stellate cells (PSCs). In a mouse model of pancreatic disease harboring elevated KRAS activity in the acinar cells, the number of activated PSCs greatly increased following the induction of pancreatitis,63 which showed that even low levels of KRAS activity could generate signals that would influence the microenvironment. In addition KRAS would maintain the stroma activated by regulating the production of factors, such as sonic hedgehog,64 IL6,31 and prostaglandin E.65 When KRAS was inactivated in low-grade PanINs, the activated fibroblasts that populated the stroma stopped expressing markers of activation, exited the cell cycle, and were eliminated from the pancreas via an unknown mechanism.46 Inactivation of KRAS also led to resolution of the chronic inflammation associated with PDA. The immune cells that infiltrated the pancreas could also be regulated by KRAS. In mouse models of PDA, tumor cells carrying mutant KRAS could secrete cytokines, such as the granulocyte-macrophage colony-stimulating factor (GM-CSF) into the microenvironment, which would promote the infiltration of myeloid-derived suppressor cells that would inhibit anti-tumor immune responses.66 As such, oncogenic KRAS could sustain the “smoldering inflammation” mostly in a paracrine manner.

Inflammation could enhance KRAS activity

Though KRAS mutation would be indispensable in pancreatic carcinogenesis, oncogenic KRAS would not be constitutively active, and the activity of KRAS would surmount a threshold to ensure its transformation ability toward the pancreatic cells. Hence, the PDA associated microenvironment would be infiltrated with different inflammatory cells, which could generate various chemokines, cytokines, and growth factors, such as IL6, IL8, IL17, tumor necrosis factor-alpha (TNF-α), microphage inhibitory factor (MIF), IL1β, transforming growth factor-beta (TGF-β), and IL10.67 All these inflammatory mediators would act on their downstream effectors in the pancreatic cells and activate those dominant oncogenes, e.g., KRAS through a paracrine manner. There would also be two core effectors, NF-κB and STAT3, connecting the inflammation and PDA. NF-kB is a nuclear transcription factor that regulates the expression of a large number of genes in response to various stimuli. NF-kB is known to be constitutively activated in most PDA patients.68 Once stressed by inflammatory stimuli, NF-kB in pancreatic cells would translocate into the nucleus, and mechanistically induce the expression of a set of downstream genes and amplify the KRAS activity.69 Like NF-kB, STAT3 would also be ubiquitously activated in most PDA cases. Activation of STAT3 could transduce upstream signals, e.g., IL6 and IL17, into the pancreatic cells and complexes with other transcription factors to sustain the KRAS activity.70 In KRAS-driven mouse models, STAT3 was a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supported cell proliferation and metaplasia-associated inflammation (Fig. 3).

The model of the “KRAS-inflammation positive feedback loop” in the PDA initiation.
Fig. 3  The model of the “KRAS-inflammation positive feedback loop” in the PDA initiation.

Inflammatory mediators would act on their downstream effectors in the pancreatic cells and activate those dominant oncogenes, e.g., KRAS, through a paracrine manner. NF-κB and STAT3 would be two core effectors connecting the inflammation and PDA. Once stressed by the inflammatory stimuli, they would mechanistically induce the expression of a set of downstream genes and amplify the KRAS activity. Then, they could also be induced as the downstream effectors of KRAS. DC, dendritic cells; IL, interleukin; KRAS, Kirsten rat sarcoma viral oncogene; MIF, microphage inhibitory factor; NF-κB, nuclear factor-κB; PDA, pancreatic ductal adenocarcinoma; STAT, signal transducer and activators of transcription; TGF-β, transforming growth factor-beta; Th, helper T cell; TNF-α, tumor necrosis factor-alpha; Treg, regulatory T cells.

The Model of “KRAS-inflammation positive feed-back loop” in PDA initiation

As KRAS mutation and inflammation are concurrent in the initial stage of PDA, it would be quite logical to assume that a “KRAS-inflammation positive feed-back loop” exists. The “KRAS-inflammation positive feedback loop” would be extremely important in sustaining the KRAS activity at a relatively high level and enhancing its transformation ability. Oncogenic KRAS in transformed PDA cells would drive the secretion of inflammatory cytokines/chemokine, thus causing the production of more cytokines and chemokines in the TME.46 These secreted factors would engage with the inflammatory receptors on the PDA cells, consequently driving a network of signaling pathways that would synergize with the oncogenic KRAS signaling in propelling the various malignant feats of PDA. Some classical inflammatory signaling pathways would include NF-kB, Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING), and MAPK. Tumor progression locus 2 (TPL2, also known as MAP3K8 or COT) is a serine-threonine protein kinase that mediates the IL1 receptor (IL1R), TLR, and TNF-dependent MAPK and NF-κB activation.71 In PDA cells, TPL2 is activated via a KRAS-MAPK driven IL1β autocrine signaling loop that engages IL1R, IRAK4, and IKKβ. In this setting, the inhibition of TPL2 would suppress MEK-ERK, p-105, and p65 NF-kB activation, hence leading to enhanced survival and chemo-resistance.72

Furthermore, oncogenic KRAS has slower kinetics of return to its guanosine diphosphate-bound status than non-oncogenic forms, which would provide extra time for activated KRAS to receive enough signals from the inflammation stimuli, and to finally generate a feedback loop that would sustain its activity. Reagents which inhibit inflammation, such as the COX2 inhibitor celecoxib, could block the feed-forward loop and prevent the induction of PDA in models with endogenous oncogenic KRAS.73-75 This model would also be supported by epidemiological reports that certain anti-inflammatory agents would be associated with a lower risk in the general population’s PDA development.

Conclusions

The “KRAS-inflammation feed-forward loop” model plays an important role in maintaining the activity of KRAS and initiation of PDA. However, pancreatic cells harboring this feed-forward loop would not be destined to become cancer cells. Thus, chronic pancreatitis (CP) would be the best model to evaluate the magnitude that the role of our proposed model would play in PDA initiation. It has also been confirmed that the incident of PDA in CP patients was obviously higher than in the general population.11 Moreover, molecular research has indicated that more than one third of the CP cases harbor KRAS mutations, whereas the incidence of PDA in CP was less than 4% in 20 years, which means as least 20% of CP cases. Though they held oncogenic KRAS cells in a harsh inflammatory milieu, this would not progress into PDA throughout their lifespan. Just as mentioned before, the loop could be blocked by immune surveillance in a normal situation. This would need the accumulation of time and other genetic promotors for the loop to maintain and eventually show a cascade amplification effect. Other important mechanisms would need to be involved in the CP to PDA progression. This would need more research about the other driver factors, as well as those noncoding RNAs that could play causal roles accompanying the “KRAS-inflammation feed-forward loop” model.

Abbreviations

CP: 

chronic pancreatitis

KRAS: 

Kirsten rat sarcoma viral oncogene

MAPK: 

mitogen-activated protein kinase

NF-κB: 

nuclear factor-κB

PanIN: 

pancreatic intraepithelial neoplasia

PDA: 

pancreatic ductal adenocarcinoma

PI3K: 

phosphoinositide 3-Kinase

STAT: 

signal transducer and activator of transcription

TME: 

tumor microenvironment

Declarations

Acknowledgement

None.

Funding

Supported in part by grant 81872043 (LL) from the National Natural Science Foundation of China; grant 82072760 (XYK) from the National Natural Science Foundation of China; National Key R&D Program of China No. 2019YFC1315900 and 2019YFC1315802.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Contribution to the study concept and design (XYK), design of the outline and supervision of the whole process (LL), and drafting of the manuscript (YF).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-249 View Article PubMed/NCBI
  2. Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol 2016;22(44):9694-9705 View Article PubMed/NCBI
  3. Reyngold M, Parikh P, Crane CH. Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results. Radiat Oncol 2019;14(1):95 View Article PubMed/NCBI
  4. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet 2020;395(10242):2008-2020 View Article PubMed/NCBI
  5. GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2019;4(12):934-947 View Article PubMed/NCBI
  6. Huang J, Lok V, Ngai CH, Zhang L, Yuan J, Lao XQ, et al. Worldwide Burden of, Risk Factors for, and Trends in Pancreatic Cancer. Gastroenterology 2021;160(3):744-754 View Article PubMed/NCBI
  7. Kirkegård J, Mortensen FV, Cronin-Fenton D. Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol 2017;112(9):1366-1372 View Article PubMed/NCBI
  8. Del Poggetto E, Ho IL, Balestrieri C, Yen EY, Zhang S, Citron F, et al. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science 2021;373(6561):eabj0486 View Article PubMed/NCBI
  9. Abbruzzese JL, Andersen DK, Borrebaeck CAK, Chari ST, Costello E, Cruz-Monserrate Z, et al. The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2018;47(5):516-525 View Article PubMed/NCBI
  10. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467(7319):1114-1117 View Article PubMed/NCBI
  11. Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021;18(7):493-502 View Article PubMed/NCBI
  12. Masamune A, Kikuta K, Hamada S, Nakano E, Kume K, Inui A, et al. Nationwide survey of hereditary pancreatitis in Japan. J Gastroenterol 2018;53(1):152-160 View Article PubMed/NCBI
  13. Gidekel Friedlander SY, Chu GC, Snyder EL, Girnius N, Dibelius G, Crowley D, et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 2009;16(5):379-389 View Article PubMed/NCBI
  14. Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11(3):291-302 View Article PubMed/NCBI
  15. Alonso-Curbelo D, Ho YJ, Burdziak C, Maag JLV, Morris JP, Chandwani R, et al. A gene-environment-induced epigenetic program initiates tumorigenesis. Nature 2021;590(7847):642-648 View Article PubMed/NCBI
  16. Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M. Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 2010;17(1):89-97 View Article PubMed/NCBI
  17. Luo Y, Li X, Ma J, Abbruzzese JL, Lu W. Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity. Cancers (Basel) 2021;13(4):778 View Article PubMed/NCBI
  18. Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 2018;215(5):1287-1299 View Article PubMed/NCBI
  19. Greten FR, Grivennikov SI. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity 2019;51(1):27-41 View Article PubMed/NCBI
  20. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591-1601 View Article PubMed/NCBI
  21. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31-41 View Article PubMed/NCBI
  22. Khalaf N, Yuan C, Hamada T, Cao Y, Babic A, Morales-Oyarvide V, et al. Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies. Gastroenterology 2018;154(5):1380-1390.e5 View Article PubMed/NCBI
  23. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461(7267):1071-1078 View Article PubMed/NCBI
  24. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-674 View Article PubMed/NCBI
  25. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140(6):883-899 View Article PubMed/NCBI
  26. Zhao B, Wang Y, Tan X, Ke K, Zheng X, Wang F, et al. Inflammatory Micro-environment Contributes to Stemness Properties and Metastatic Potential of HCC via the NF-κB/miR-497/SALL4 Axis. Mol Ther Oncolytics 2019;15:79-90 View Article PubMed/NCBI
  27. Wang L, Guo J, Zhou J, Wang D, Kang X, Zhou L. NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497-5p and upregulating MCM2. J Exp Clin Cancer Res 2020;39(1):225 View Article PubMed/NCBI
  28. Jia L, Wang Y, Wang CY. circFAT1 Promotes Cancer Stemness and Immune Evasion by Promoting STAT3 Activation. Adv Sci (Weinh) 2021;8(13):2003376 View Article PubMed/NCBI
  29. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 2009;16(2):91-102 View Article PubMed/NCBI
  30. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 2010;21(1):11-19 View Article PubMed/NCBI
  31. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19(4):456-469 View Article PubMed/NCBI
  32. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118(3):285-296 View Article PubMed/NCBI
  33. Panigrahy D, Gartung A, Yang J, Yang H, Gilligan MM, Sulciner ML, et al. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases. J Clin Invest 2019;129(7):2964-2979 View Article PubMed/NCBI
  34. Swidnicka-Siergiejko AK, Gomez-Chou SB, Cruz-Monserrate Z, Deng D, Liu Y, Huang H, et al. Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53. Oncogene 2017;36(22):3149-3158 View Article PubMed/NCBI
  35. Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, et al. The natural history of hereditary pancreatitis: a national series. Gut 2009;58(1):97-103 View Article PubMed/NCBI
  36. Whitcomb DC, Shelton CA, Brand RE. Genetics and Genetic Testing in Pancreatic Cancer. Gastroenterology 2015;149(5):1252-1264.e4 View Article PubMed/NCBI
  37. Cotterchio M, Lowcock E, Hudson TJ, Greenwood C, Gallinger S. Association between allergies and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2014;23(3):469-480 View Article PubMed/NCBI
  38. Park B, Yoon J, Choi D, Kim HJ, Jung YK, Kwon OJ, et al. De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data. Sci Rep 2019;9(1):17202 View Article PubMed/NCBI
  39. Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer 2009;125(8):1747-1754 View Article PubMed/NCBI
  40. Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022;22(7):397-413 View Article PubMed/NCBI
  41. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518(7540):495-501 View Article PubMed/NCBI
  42. Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M, et al. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov 2018;8(9):1096-1111 View Article PubMed/NCBI
  43. Löhr M, Klöppel G, Maisonneuve P, Lowenfels AB, Lüttges J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 2005;7(1):17-23 View Article PubMed/NCBI
  44. Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142(4):730-733.e9 View Article PubMed/NCBI
  45. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4(6):437-450 View Article PubMed/NCBI
  46. di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 2013;144(6):1220-1229 View Article PubMed/NCBI
  47. Collins MA, Yan W, Sebolt-Leopold JS, Pasca di Magliano M. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 2014;146(3):822-834.e7 View Article PubMed/NCBI
  48. Jonckheere N, Vasseur R, Van Seuningen I. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting. Crit Rev Oncol Hematol 2017;111:7-19 View Article PubMed/NCBI
  49. Lim KH, O’Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol 2006;16(24):2385-2394 View Article PubMed/NCBI
  50. Taniuchi K, Furihata M, Hanazaki K, Iwasaki S, Tanaka K, Shimizu T, et al. Peroxiredoxin 1 promotes pancreatic cancer cell invasion by modulating p38 MAPK activity. Pancreas 2015;44(2):331-340 View Article PubMed/NCBI
  51. Okada M, Shibuya K, Sato A, Seino S, Suzuki S, Seino M, et al. Targeting the K-Ras—JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. Oncotarget 2014;5(13):5100-5112 View Article PubMed/NCBI
  52. Han D, Zhu S, Li X, Li Z, Huang H, Gao W, et al. The NF-κB/miR-488/ERBB2 axis modulates pancreatic cancer cell malignancy and tumor growth through cell cycle signaling. Cancer Biol Ther 2022;23(1):294-309 View Article PubMed/NCBI
  53. Mann KM, Ying H, Juan J, Jenkins NA, Copeland NG. KRAS-related proteins in pancreatic cancer. Pharmacol Ther 2016;168:29-42 View Article PubMed/NCBI
  54. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020;17(3):153-168 View Article PubMed/NCBI
  55. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev 2020;39(4):1029-1038 View Article PubMed/NCBI
  56. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410(6832):1111-1116 View Article PubMed/NCBI
  57. Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 2004;5(4):375-387 View Article PubMed/NCBI
  58. Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 2003;4(2):111-120 View Article PubMed/NCBI
  59. Huang H, Daniluk J, Liu Y, Chu J, Li Z, Ji B, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene 2014;33(4):532-535 View Article PubMed/NCBI
  60. Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012;22(3):304-317 View Article PubMed/NCBI
  61. Navas C, Hernández-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 2012;22(3):318-330 View Article PubMed/NCBI
  62. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther 2021;6(1):263 View Article PubMed/NCBI
  63. Won JH, Zhang Y, Ji B, Logsdon CD, Yule DI. Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis. Mol Biol Cell 2011;22(3):421-436 View Article PubMed/NCBI
  64. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457-1461 View Article PubMed/NCBI
  65. Charo C, Holla V, Arumugam T, Hwang R, Yang P, Dubois RN, et al. Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. Pancreas 2013;42(3):467-474 View Article PubMed/NCBI
  66. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21(6):836-847 View Article PubMed/NCBI
  67. Roshani R, McCarthy F, Hagemann T. Inflammatory cytokines in human pancreatic cancer. Cancer Lett 2014;345(2):157-163 View Article PubMed/NCBI
  68. Li Q, Yang G, Feng M, Zheng S, Cao Z, Qiu J, et al. NF-κB in pancreatic cancer: Its key role in chemoresistance. Cancer Lett 2018;421:127-134 View Article PubMed/NCBI
  69. Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest 2012;122(4):1519-1528 View Article PubMed/NCBI
  70. Baumgart S, Chen NM, Siveke JT, König A, Zhang JS, Singh SK, et al. Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 2014;4(6):688-701 View Article PubMed/NCBI
  71. Pattison MJ, Mitchell O, Flynn HR, Chen CS, Yang HT, Ben-Addi H, et al. TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. Biochem J 2016;473(18):2845-2861 View Article PubMed/NCBI
  72. Dodhiawala PB, Khurana N, Zhang D, Cheng Y, Li L, Wei Q, et al. TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations. J Clin Invest 2020;130(9):4771-4790 View Article PubMed/NCBI
  73. Karmakar S, Kaushik G, Nimmakayala R, Rachagani S, Ponnusamy MP, Batra SK. MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin Cancer Biol 2019;54:63-71 View Article PubMed/NCBI
  74. Lanfredini S, Thapa A, O’Neill E. RAS in pancreatic cancer. Biochem Soc Trans 2019;47(4):961-972 View Article PubMed/NCBI
  75. Logsdon CD, Lu W. The Significance of Ras Activity in Pancreatic Cancer Initiation. Int J Biol Sci 2016;12(3):338-346 View Article PubMed/NCBI
  • Cancer Screening and Prevention
  • pISSN 2993-6314
  • eISSN 2835-3315
Back to Top

The Positive Feedback Loop Between Inflammation and Mutant KRAS Genes Promotes Malignant Transformation in Chronic Pancreatitis

Fan Yang, Lei Li, Xiang-Yu Kong
  • Reset Zoom
  • Download TIFF