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PIES Cancer Hypothesis
E-Cancer June 2018
2. CTO (Springer nature initiative ): “Do locally advanced and metastatic human epithelial cancers evolve in ‘placental/decidual-like microenvironments’?” in Clinical and Translational Oncology.
1. Genomics paper: “Placental immune editing switch (PIES): learning about immunomodulatory pathways from a unique case report”
Oncotarget. 2016; 7:83817-83827. https://doi.org/10.18632/oncotarget.13306
Miguel H. Bronchud1, Francesc Tresserra2, Wenjie Xu3, Sarah Warren3, Maite Cusido4, Bernat Zantop5, Ana Claudia Zenclussen6 and Alessandra Cesano3
1 Institut Bellmunt Oncologia, Hospital Universitario Dexeus. Grupo Quirón Salud, Barcelona, Spain
2 Servei Anatomia Patològica, Hospital Universitario Dexeus. Grupo Quirón Salud, Barcelona, Spain
3 Nanostring Technologies, Immune Oncology, Seattle, WA, USA
4 Ginecologia Oncològica, Hospital Universitario Dexeus. Grupo Quirón Salud, Barcelona, Spain
5 Servei Obstetricia i Neonatologia, Hospital Universitario Dexeus. Grupo Quirón Salud, Barcelona, Spain
6 Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
Miguel H. Bronchud, email: firstname.lastname@example.org
Keywords: materno-fetal tolerance, cancer microenvironment, placental microenvironment, immune vigilance, carcinogenesis
Received: July 11, 2016 Accepted: October 25, 2016 Published: November 11, 2016
The hypothesis of this work is that, in order to escape the natural immune surveillance mechanisms, cancer cells and the surrounding microenvironment might express ectopically genes that are physiologically present in the placenta to mediate fetal immune-tolerance. These natural “placental immune-editing switch” mechanisms (PIES) may represent the result of millions of years of mammalian evolution developed to allow materno-fetal tolerance. Here, we introduce genes of the immune regulatory pathways that are either similarly over- or under-expressed in tumor vs normal tissue. Our analysis was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman. Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (in the placenta) and pathologically (in the cancer setting).
2. Epigenetic Paper: “Epigenetic changes found in uterine decidual and placental tissues can also be found in the breast cancer microenvironment of the same unique patient: description and potential interpretations”. By Miguel H. Bronchud, Francesc Tresserra, and Bernat Serra Zantop.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814192/#__ffn_sectitle Here we report the first epigenomic analysis of these tissue samples and describe their main findings, with respect to immune related genes regulation (over or under expressed) in cancer cells with regards placental tissues. We confirm significant similarities, and hierarchical clustering (both unsupervised and supervised), in CpG island methylation patterns between decidual/placental and cancer microenvironments, which cannot be easily explained by simple models or unique pathways. Several different cell types are probably involved in these complex immune regulation mechanisms. Cancers may somehow “hijack” gene programs evolved over millions of years to allow for feto-maternal tolerance in placental mammals in order to escape from immune vigilance and spread locally or to distant sites.
3. Immunology Abstracts as published in Journal of Clinical Oncology at ASCO-2017/ http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.7_suppl.13
Background: cancers might partially ectopically express intrinsic immune escape gene programs naturally developed during mammalian evolution to allow for materno-fetal immune tolerance. Methods: Genomic analysis (Nanostring Inc, Seattle, WA, USA) was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman (same patient). Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Results: Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (placenta) and pathologically ( cancer). Placenta and uterus, breast tissues (tumor and normal) and lymph node tissues (tumor and normal) formed their own RNA transcription cluster, suggesting that tissue specific gene expression patterns were well preserved during experimental procedures . We analyzed differential expression within each tissue type (i.e. matching for the analysis placenta with uterus, breast cancer with normal breast tissue and node positive with node negative tissue). Among the 583 genes analyzed, 103 genes were upregulated > 1.5 fold in placenta versus uterus, while 258 genes were downregulated at least 1.5 fold. Using the same cut-off, 258 genes were upregulated and 44 genes downregulated in breast tumor versus normal breast tissue, and 178 genes were upregulated while 146 genes downregulated in tumor bearing lymph node versus non-involved lymph node. Conclusions: A variety of complex immune regulation mechanisms seem to be shared by both placental tissues and cancer.
Explanation of the implications of PIES hypothesis
1. From an evolutionary point of view: cancer as a disease of placental mammals (Eutheria): Placental immune editing switches (PIES) have not evolved to prevent or to cause cancer but to make feto-maternal immune tolerance possible, which is at the very core of our placental mammalian (‘Eutherian’) nature. Aggressive epithelial cancers might be an unfortunate ‘side effect’ of this highly sophisticated biological nature. Microenvironmental properties in the placenta and decidua are thought to be a key to feto-maternal immune tolerance. Recently, in 2016–2018, we published the first human genomic and epigenomic evidence of similar gene expression profiles in immune regulatory genes in cancer (primary lobular infiltrating breast cancer and ipsilateral axillary metastatic lymph nodes) and both placenta and decidua of the same young patient with breast carcinoma during pregnancy. These findings led us to speculate that ectopic expression, or repression, of ‘PIES’ might be used by cancer cells during carcinogenesis or cancer progression to elude immune vigilance in spite of tumour-associated antigens or evolving neo antigenic landscapes. Cancers are well known to frequently express embryonic antigens, such as carcinoembryonic antigen, used as cancer markers and detectable in the blood circulation, or to express ectopic hormones. Why should cancer cells invent de novo complex new immune suppression mechanisms, if they could simply use innate ones developed during the long-term evolution of placental mammals in order to hide fetal paternal antigens from the mother’s own immune system?
Monotremata (Prototheria-like Echidnas or Platypus Ornithoryncus) are nonplacental egg-laying mammals and, in spite of rudimentary breast epithelial ducts and lobules, they are seldom reported to suffer from aggressive breast cancers.
Published by Miguel Hernandez-Bronchud in Ecancer , June 2018
2. From a tumor microenvironments point of view:
Dear Olivia Campbell
Congratulations for paying due attention to this still “fringe cancer research work “. As mainly a Cancer Clinician since 1983(and having published my first book on Cancer Pathogenesis in Spanish in 1978, Biblioteca Nacional de Madrid) I published my Placental Immune Editing Switches Hypothesis back in 2015 (first in Research Gate and then in two Oncotarget papers 2016 and 2017-8; as well as in JCO (as ASCO abstract meeting) and in 2018 in E-cancer and Springer Clinical and Translational Oncology ; providing not only a full theoretical background but also the first clinical evidence on both genomics (Nanostring Technology) and Epigenetic CpG islands methylation.
This relationship was suggested over twenty years ago in an article in the journal Molecular Human Reproduction (https://www.ncbi.nlm.nih.gov/pubmed/9239703). This article was designated as an Outstanding Contribution by the Editor of this journal at that time (Nobel Laureate Robert G. Edwards, Physiology or Medicine, 2010). A model for the protection of the developing human known as the Human Fetoembryonic Defense System (Hu-FEDS) Hypothesis was presented in this paper. A novel cancer therapy based on the Hu-FEDS hypothesis has recently been developed and tested in dogs. Complete remissions of aggressive canine cancers have been documented without the induction of any side effects. The results of this clinical trial were presented at a Veterinary Cancer Society meeting in October, 2017. These findings have also been summarized in a video on You Tube beginning at the 17:40 minute mark: https://www.youtube.com/watch?v=NB3fqg9z5-4. Based on these encouraging results, my collaborator Dr. Jeff Bryan and I are trying to initiate a clinical trial in human patients. In summary, the relationship between pregnancy and cancer discussed in this news story is not only well established, but is being employed to actively attack and destroy tumor cells.