Field cancerization is the process by which carcinogenic insults cause genetic and epigenetic alterations in the tissue field, predisposing it to cancer. Current mereological, temporally synchronic explanatory paradigms struggle to explain why the complete clearance of malignant cells in the field is so often followed by local recurrence. We argue that a more complete account requires a process-ontological framework that captures both synchronic reflexive causation across levels of organization and the diachronic constitution of tissue states by their histories. We formalize these conceptual ideas using a mathematical model that tracks the frequencies of normal and malignant cells and the levels of tissue damage, resilience, and semiotic corruption. We derive a closed-form expression for the escape crossover, which specifies the level of semiotic corruption under which malignant cells acquire a fitness advantage over normal cells. We find that the system exhibits hysteresis, thereby requiring significantly more effort to destabilize a malignant state than to maintain the system at homeostasis. We identify regions of the state space that guarantee malignant escape or containment, and demonstrate a connection between repeated injuries and chronic disease, which tilts the system's disposition towards malignancy. We show that although tissues effectively recover from acute injuries, repeated insults accumulate tissue damage, erode resilience, promote semiotic corruption, and eventually trigger malignant escape. Surgery, even if it clears all malignant cells, leaves the tissue in poor health with semiosis corrupted and leads to recurrence. On the other hand, field-directed therapies restore tissue health and semiotic integrity, leading to durable responses and tissue normalcy. These findings reframe field cancerization as an inherently multi-scale phenomenon of semiotic corruption whose present state is actively constituted by traces from the past.
Citation: Anuraag Bukkuri. Hauntings in the field: The evolutionary dynamics of semiotic corruption and tissue normativity in carcinogenesis[J]. Mathematical Biosciences and Engineering, 2026, 23(9): 2698-2719. doi: 10.3934/mbe.2026097
Field cancerization is the process by which carcinogenic insults cause genetic and epigenetic alterations in the tissue field, predisposing it to cancer. Current mereological, temporally synchronic explanatory paradigms struggle to explain why the complete clearance of malignant cells in the field is so often followed by local recurrence. We argue that a more complete account requires a process-ontological framework that captures both synchronic reflexive causation across levels of organization and the diachronic constitution of tissue states by their histories. We formalize these conceptual ideas using a mathematical model that tracks the frequencies of normal and malignant cells and the levels of tissue damage, resilience, and semiotic corruption. We derive a closed-form expression for the escape crossover, which specifies the level of semiotic corruption under which malignant cells acquire a fitness advantage over normal cells. We find that the system exhibits hysteresis, thereby requiring significantly more effort to destabilize a malignant state than to maintain the system at homeostasis. We identify regions of the state space that guarantee malignant escape or containment, and demonstrate a connection between repeated injuries and chronic disease, which tilts the system's disposition towards malignancy. We show that although tissues effectively recover from acute injuries, repeated insults accumulate tissue damage, erode resilience, promote semiotic corruption, and eventually trigger malignant escape. Surgery, even if it clears all malignant cells, leaves the tissue in poor health with semiosis corrupted and leads to recurrence. On the other hand, field-directed therapies restore tissue health and semiotic integrity, leading to durable responses and tissue normalcy. These findings reframe field cancerization as an inherently multi-scale phenomenon of semiotic corruption whose present state is actively constituted by traces from the past.
| [1] |
D. P. Slaughter, H. W. Southwick, W. Smejkal, "Field cancerization" in oral stratified squamous epithelium. Clinical implications of multicentric origin, Cancer, 6 (1953), 963–968. https://doi.org/10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q doi: 10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q
|
| [2] |
P. K. Ha, J. A. Califano, The molecular biology of mucosal field cancerization of the head and neck, Crit. Rev. Oral Biol. Med., 14 (2003), 363–369. https://doi.org/10.1177/154411130301400506 doi: 10.1177/154411130301400506
|
| [3] | M. G. Van Oijen, P. J. Slootweg, Oral field cancerization: Carcinogen-induced independent events or micrometastatic deposits? Cancer Epidemiol. Biomarkers Prev., 9 (2000), 249–256. |
| [4] |
P. C. Galipeau, L. J. Prevo, C. A. Sanchez, G. M. Longton, B. J. Reid, Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue, J. Natl. Cancer Inst., 91 (1999), 2087–2095. https://doi.org/10.1093/jnci/91.24.2087 doi: 10.1093/jnci/91.24.2087
|
| [5] | L. J. Prevo, C. A. Sanchez, P. C. Galipeau, B. J. Reid, p53-mutant clones and field effects in Barrett's esophagus, Cancer Res., 59 (1999), 4784–4787. |
| [6] |
S. E. Durham, K. J. Krishnan, J. Betts, M. A. Birch-Machin, Mitochondrial DNA damage in non-melanoma skin cancer, Br. J. Cancer, 88 (2003), 90–95. https://doi.org/10.1038/sj.bjc.6600773 doi: 10.1038/sj.bjc.6600773
|
| [7] |
A. Eshaghian, R. A. Vleugels, J. A. Canter, M. A. McDonald, T. Stasko, J. E. Sligh, Mitochondrial DNA deletions serve as biomarkers of aging in the skin, but are typically absent in nonmelanoma skin cancers, J. Invest. Dermatol., 126 (2006), 336–344. https://doi.org/10.1038/sj.jid.5700088 doi: 10.1038/sj.jid.5700088
|
| [8] | S. Kanjilal, S. S. Strom, G. L. Clayman, R. S. Weber, A. K. El-Naggar, V. Kapur, et al., p53 mutations in nonmelanoma skin cancer of the head and neck: Molecular evidence for field cancerization, Cancer Res., 55 (1995), 3604–3609. |
| [9] |
W. A. Franklin, A. F. Gazdar, J. Haney, I. I. Wistuba, F. G. La Rosa, T. Kennedy, et al., Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis, J. Clin. Invest., 100 (1997), 2133–2137. https://doi.org/10.1172/JCI119748 doi: 10.1172/JCI119748
|
| [10] |
H. Pan, J. Califano, J. F. Ponte, A. L. Russo, K. H. Cheng, A. Thiagalingam, et al., Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer, Cancer Res., 65 (2005), 1664–1669. https://doi.org/10.1158/0008-5472.CAN-04-3297 doi: 10.1158/0008-5472.CAN-04-3297
|
| [11] |
I. W. Park, I. I. Wistuba, A. Maitra, S. Milchgrub, A. K. Virmani, J. D. Minna, et al., Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer, J. Natl. Cancer Inst., 91 (1999), 1863–1868. https://doi.org/10.1093/jnci/91.21.1863 doi: 10.1093/jnci/91.21.1863
|
| [12] |
W. M. Grady, Epigenetic events in the colorectum and in colon cancer, Biochem. Soc. Trans., 33 (2005), 684–688. https://doi.org/10.1042/BST0330684 doi: 10.1042/BST0330684
|
| [13] |
S. Jothy, B. Ślesak, A. Harłozińska, J. Lapińska, J. Adarniak, J. Rabczyński, Field effect of human colon carcinoma on normal mucosa: Relevance of carcinoembryonic antigen expression, Tumor Biol., 17 (1996), 58–64. https://doi.org/10.1159/000217967 doi: 10.1159/000217967
|
| [14] |
J. Y. Wang, Y. H. Wang, S. W. Jao, C. Y. Lu, C. H. Kuo, H. M. Hu, et al., Molecular mechanisms underlying the tumorigenesis of colorectal adenomas: Correlation to activated K-ras oncogene, Oncol. Rep., 16 (2006), 1245–1252. https://doi.org/10.3892/or.16.6.1245 doi: 10.3892/or.16.6.1245
|
| [15] |
J. S. Kim, C. W. Choi, B. S. Kim, S. W. Shin, Y. H. Kim, Y. J. Mok, et al., Amplification of c-erbB-2 proto-oncogene in cancer foci, adjacent normal, metastatic and normal tissues of human primary gastric adenocarcinomas, J. Korean Med. Sci., 12 (1997), 311–315. https://doi.org/10.3346/jkms.1997.12.4.311 doi: 10.3346/jkms.1997.12.4.311
|
| [16] |
J. Y. Kim, H. J. Cho, DNA ploidy patterns in gastric adenocarcinoma, J. Korean Med. Sci., 15 (2000), 159–166. https://doi.org/10.3346/jkms.2000.15.2.159 doi: 10.3346/jkms.2000.15.2.159
|
| [17] |
S. K. Kim, H. R. Jang, J. H. Kim, S. M. Noh, K. S. Song, M. R. Kim, et al., The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration, Biochem. Biophys. Res. Commun., 349 (2006), 1032–1040. https://doi.org/10.1016/j.bbrc.2006.08.128 doi: 10.1016/j.bbrc.2006.08.128
|
| [18] |
M. Tang, S. Baez, M. Pruyas, A. Diaz, A. Calvo, E. Riquelme, et al., Mitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma, Clin. Cancer Res., 10 (2004), 1041–1046. https://doi.org/10.1158/1078-0432.CCR-0701-3 doi: 10.1158/1078-0432.CCR-0701-3
|
| [19] |
R. Dhir, B. Vietmeier, J. Arlotti, M. Acquafondata, D. Landsittel, R. Masterson, et al., Early identification of individuals with prostate cancer in negative biopsies, J. Urol., 171 (2004), 1419–1423. https://doi.org/10.1097/01.ju.0000116545.94813.27 doi: 10.1097/01.ju.0000116545.94813.27
|
| [20] |
H. Uetsuki, H. Tsunemori, R. Taoka, R. Haba, M. Ishikawa, Y. Kakehi, Expression of a novel biomarker, EPCA, in adenocarcinomas and precancerous lesions in the prostate, J. Urol., 174 (2005), 514–518. https://doi.org/10.1097/01.ju.0000165154.41159.b1 doi: 10.1097/01.ju.0000165154.41159.b1
|
| [21] |
Y. P. Yu, D. Landsittel, L. Jing, J. Nelson, B. Ren, L. Liu, et al., Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy, J. Clin. Oncol., 22 (2004), 2790–2799. https://doi.org/10.1200/JCO.2004.05.158 doi: 10.1200/JCO.2004.05.158
|
| [22] |
T. Izawa, T. Obara, S. Tanno, Y. Mizukami, N. Yanagawa, Y. Kohgo, Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas, Cancer, 92 (2001), 1807–1817. https://doi.org/10.1002/1097-0142(20011001)92:7<1807::AID-CNCR1697>3.0.CO;2-0 doi: 10.1002/1097-0142(20011001)92:7<1807::AID-CNCR1697>3.0.CO;2-0
|
| [23] |
T. Y. Chu, C. Y. Shen, H. S. Lee, H. S. Liu, Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: A local field effect of genomic instability and clonal evolution, Genes, Chromosomes Cancer, 24 (1999), 12–134. https://doi.org/10.1002/(SICI)1098-2264(199902)24:2<127::AID-GCC5>3.0.CO;2-8 doi: 10.1002/(SICI)1098-2264(199902)24:2<127::AID-GCC5>3.0.CO;2-8
|
| [24] |
A. N. Rosenthal, A. Ryan, D. Hopster, I. J. Jacobs, Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases, Int. J. Cancer, 99 (2002), 549–554. https://doi.org/10.1002/ijc.10362 doi: 10.1002/ijc.10362
|
| [25] |
R. E. Buller, J. S. Skilling, A. K. Sood, S. Plaxe, R. N. Baergen, D. J. Lager, Field cancerization: Why late "recurrent'' ovarian cancer is not recurrent, Am. J. Obstet. Gynecol., 178 (1998), 641–649. https://doi.org/10.1016/S0002-9378(98)70473-9 doi: 10.1016/S0002-9378(98)70473-9
|
| [26] | B. H. Ortiz, C. Colitti, S. C. Mok, M. Ailawadi, M. G. Muto, R. S. Berkowitz, et al., Second primary or recurrence? Comparative patterns of p53 and K-ras mutations suggest that serous borderline ovarian tumors and subsequent serous carcinomas are unrelated tumors, Cancer Res., 61 (2001), 7264–7267. |
| [27] |
M. Amari, T. Moriya, T. Ishida, Y. Harada, K. Ohnuki, M. Takeda, et al., Loss of heterozygosity analyses of asynchronous lesions of ductal carcinoma in situ and invasive ductal carcinoma of the human breast, Jpn. J. Clin. Oncol., 33 (2003), 556–562. https://doi.org/10.1093/jjco/hyg109 doi: 10.1093/jjco/hyg109
|
| [28] |
D. L. Ellsworth, R. E. Ellsworth, B. Love, B. Deyarmin, S. M. Lubert, V. Mittal, et al., Outer breast quadrants demonstrate increased levels of genomic instability, Ann. Surg. Oncol., 11 (2004), 861–868. https://doi.org/10.1245/ASO.2004.03.024 doi: 10.1245/ASO.2004.03.024
|
| [29] |
D. M. Euhus, L. Cler, N. Shivapurkar, S. Milchgrub, G. N. Peters, A. M. Leitch, et al., Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk, J. Natl. Cancer Inst., 94 (2002), 858–860. https://doi.org/10.1093/jnci/94.11.858 doi: 10.1093/jnci/94.11.858
|
| [30] | T. Takahashi, T. Habuchi, Y. Kakehi, K. Mitsumori, T. Akao, T. Terachi, et al., Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract, Cancer Res., 58 (1998), 5835–5841. |
| [31] |
G. D. Dakubo, J. P. Jakupciak, M. A. Birch-Machin, R. L. Parr, Clinical implications and utility of field cancerization, Cancer Cell Int., 7 (2007), 2. https://doi.org/10.1186/1475-2867-7-2 doi: 10.1186/1475-2867-7-2
|
| [32] |
A. S. Pierik, C. R. Leemans, R. H. Brakenhoff, Resection margins in head and neck cancer surgery: An update of residual disease and field cancerization, Cancers, 13 (2021), 2635. https://doi.org/10.3390/cancers13112635 doi: 10.3390/cancers13112635
|
| [33] | M. P. Tabor, R. H. Brakenhoff, V. M. van Houten, J. A. Kummer, M. H. Snel, P. J. Snijders, et al., Persistence of genetically altered fields in head and neck cancer patients: Biological and clinical implications, Clin. Cancer Res., 7 (2001), 1523–1532. |
| [34] |
L. B. Alexandrov, S. Nik-Zainal, D. C. Wedge, S. A. J. R. Aparicio, S. Behjati, A. V. Biankin, et al., Signatures of mutational processes in human cancer, Nature, 500 (2013), 415–421. https://doi.org/10.1038/nature12477 doi: 10.1038/nature12477
|
| [35] |
D. L. Vaux, In defense of the somatic mutation theory of cancer, BioEssays, 33 (2011), 341–343. https://doi.org/10.1002/bies.201100022 doi: 10.1002/bies.201100022
|
| [36] |
S. Huang, A. M. Soto, C. Sonnenschein, The end of the genetic paradigm of cancer, PLoS Biol., 23 (2025), e3003052. https://doi.org/10.1371/journal.pbio.3003052 doi: 10.1371/journal.pbio.3003052
|
| [37] |
C. Sonnenschein, A. M. Soto, Somatic mutation theory of carcinogenesis: Why it should be dropped and replaced, Mol. Carcinog., 29 (2000), 205–211. https://doi.org/10.1002/1098-2744(200012)29:4<205::AID-MC1002>3.0.CO;2-W doi: 10.1002/1098-2744(200012)29:4<205::AID-MC1002>3.0.CO;2-W
|
| [38] | G. Simondon, T. Adkins, Individuation in Light of Notions of Form and Information, University of Minnesota Press, 2020. |
| [39] | G. Canguilhem, On the Normal and the Pathological, Springer Netherlands, Dordrecht, 1978. https://doi.org/10.1007/978-94-009-9853-7 |
| [40] |
A. Bukkuri, F. R. Adler, Of criminals and cancer: The importance of social bonds and innate morality on cellular societies, Cells Dev., 180 (2024), 203964. https://doi.org/10.1016/j.cdev.2024.203964 doi: 10.1016/j.cdev.2024.203964
|
| [41] | B. Krickel, Different types of mechanistic explanation and their ontological implications, in New Mechanism, Springer, (2024), 9–28. https://doi.org/10.1007/978-3-031-46917-6_2 |
| [42] | J. Derrida, Specters of Marx: the State of the Debt, the Work of Mourning and the New International, Routledge, New York, 2006. https://doi.org/10.4324/9780203821619 |
| [43] | C. S. Peirce, Collected Papers of Charles Sanders Peirce, Harvard University Press, 1934. |
| [44] |
J. Foo, K. Leder, M. D. Ryser, Multifocality and recurrence risk: A quantitative model of field cancerization, J. Theor. Biol., 355 (2014), 170–184. https://doi.org/10.1016/j.jtbi.2014.02.042 doi: 10.1016/j.jtbi.2014.02.042
|
| [45] |
J. Foo, E. B. Gunnarsson, K. Leder, K. Storey, Spread of premalignant mutant clones and cancer initiation in multilayered tissue, Ann. Appl. Probab., 33 (2023), 299-343. https://doi.org/10.1214/22-AAP1816 doi: 10.1214/22-AAP1816
|
| [46] |
M. D. Ryser, W. T. Lee, N. E. Ready, K. Z. Leder, J. Foo, Quantifying the dynamics of field cancerization in tobacco-related head and neck cancer: A multiscale modeling approach, Cancer Res., 76 (2016), 7078–7088. https://doi.org/10.1158/0008-5472.CAN-16-1054 doi: 10.1158/0008-5472.CAN-16-1054
|
| [47] |
M. Takaki, H. Haeno, Mathematical modeling of locoregional recurrence caused by premalignant lesions formed before initial treatment, Front. Oncol., 11 (2021), 743328. https://doi.org/10.3389/fonc.2021.743328 doi: 10.3389/fonc.2021.743328
|
| [48] |
K. Deutscher, T. Hillen, J. Newby, A computational model for the cancer field effect, Front. Artif. Intell., 6 (2023), 1060879. https://doi.org/10.3389/frai.2023.1060879 doi: 10.3389/frai.2023.1060879
|
| [49] |
E. N. Arwert, E. Hoste, F. M. Watt, Epithelial stem cells, wound healing and cancer, Nat. Rev. Cancer, 12 (2012), 170–180. https://doi.org/10.1038/nrc3217 doi: 10.1038/nrc3217
|
| [50] |
C. Blanpain, E. Fuchs, Plasticity of epithelial stem cells in tissue regeneration, Science, 344 (2014), 6189. https://doi.org/10.1126/science.124228 doi: 10.1126/science.124228
|
| [51] |
S. Dekoninck, C. Blanpain, Stem cell dynamics, migration and plasticity during wound healing, Nat. Cell Biol., 21 (2019), 18–24. https://doi.org/10.1038/s41556-018-0237-6 doi: 10.1038/s41556-018-0237-6
|
| [52] |
G. P. Dotto, Multifocal epithelial tumors and field cancerization: Stroma as a primary determinant, J. Clin. Invest., 124 (2014), 1446–1453. https://doi.org/10.1172/JCI72589 doi: 10.1172/JCI72589
|
| [53] |
R. Medzhitov, D. S. Schneider, M. P. Soares, Disease tolerance as a defense strategy, Science, 335 (2012). https://doi.org/10.1126/science.1214935 doi: 10.1126/science.1214935
|
| [54] |
M. J. Allegrezza, M. R. Rutkowski, T. L. Stephen, N. Svoronos, A. Perales-Puchalt, J. M. Nguyen, et al., Trametinib drives T-cell-dependent control of KRAS-mutated tumors by inhibiting pathological myelopoiesis, Cancer Res., 76 (2016), 6253–6265. https://doi.org/10.1158/0008-5472.CAN-16-1308 doi: 10.1158/0008-5472.CAN-16-1308
|
| [55] |
E. Brogi, F. Forfori, Anesthesia and cancer recurrence: an overview, J. Anesth. Analg. Crit. Care, 2 (2022), 33. https://doi.org/10.1186/s44158-022-00060-9 doi: 10.1186/s44158-022-00060-9
|
| [56] |
X. Cheng, H. Zhang, A. Hamad, H. Huang, A. Tsung, Surgery-mediated tumor-promoting effects on the immune microenvironment, Semin. Cancer Biol., 86 (2022), 408–419. https://doi.org/10.1016/j.semcancer.2022.01.006 doi: 10.1016/j.semcancer.2022.01.006
|
| [57] |
N. E. Donlon, M. Davern, C. Hayes, R. Power, A. D. Sheppard, C. L. Donohoe, et al., The immune response to major gastrointestinal cancer surgery and potential implications for adjuvant immunotherapy, Crit. Rev. Oncol. Hematol., 175 (2022), 103729. https://doi.org/10.1016/j.critrevonc.2022.103729 doi: 10.1016/j.critrevonc.2022.103729
|
| [58] |
F. Tang, Y. Tie, C. Tu, X. Wei, Surgical trauma-induced immunosuppression in cancer: Recent advances and the potential therapies, Clin. Transl. Med., 10 (2020), 199–223. https://doi.org/10.1002/ctm2.24 doi: 10.1002/ctm2.24
|
| [59] |
S. Tohme, R. L. Simmons, A. Tsung, Surgery for cancer: A trigger for metastases, Cancer Res., 77 (2017), 1548–1552. https://doi.org/10.1158/0008-5472.CAN-16-1536 doi: 10.1158/0008-5472.CAN-16-1536
|
| [60] |
M. D. Brown, R. van der Most, J. B. Vivian, R. A. Lake, I. Larma, B. W. S. Robinson, et al., Loss of antigen cross-presentation after complete tumor resection is associated with the generation of protective tumor-specific CD8 $^{+}$ T-cell immunity, OncoImmunology, 1 (2012), 1084–1094. https://doi.org/10.4161/onci.20924 doi: 10.4161/onci.20924
|
| [61] |
A. Kaskas, P. Clavijo, J. Friedman, M. Craveiro, C. T. Allen, Complete tumor resection reverses neutrophilia-associated suppression of systemic anti-tumor immunity, Oral Oncol., 150 (2024), 106705. https://doi.org/10.1016/j.oraloncology.2024.106705 doi: 10.1016/j.oraloncology.2024.106705
|
| [62] |
T. Eckschlager, J. Plch, M. Stiborova, J. Hrabeta, Histone deacetylase inhibitors as anticancer drugs, Int. J. Mol. Sci., 18 (2017), 1414. https://doi.org/10.3390/ijms18071414 doi: 10.3390/ijms18071414
|
| [63] | H. J. Kim, S. C. Bae, Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anti-cancer drugs, Am. J. Transl. Res., 3 (2011), 166–179. |
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Anuraag Bukkuri. Hauntings in the field: The evolutionary dynamics of semiotic corruption and tissue normativity in carcinogenesis[J]. Mathematical Biosciences and Engineering, 2026, 23(9): 2698-2719. doi: 10.3934/mbe.2026097
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