Frank McKeon

The Jackson Laboratory, BHB, Maine, United States

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Publications (138)1810.63 Total impact

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    ABSTRACT: High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the fallopian tube, termed "serous tubal intraepithelial carcinoma" or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs) and lower grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed fallopian tube stem cells (FTSC). We demonstrated that pedigrees of FTSCs were capable of multi-potent differentiation and that the tumors derived from transformed FTSC shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (Stathmin, EZH2, CXCR4, CXCL12 and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSC, immortalized FTSC, and transformed FTSC showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multi-potent FTSCs.
    The Journal of Pathology 09/2015; DOI:10.1002/path.4649 · 7.43 Impact Factor

  • Clinical Cancer Research 08/2015; 21(16 Supplement):POSTER-TECH-1121-POSTER-TECH-1121. DOI:10.1158/1557-3265.OVCASYMP14-POSTER-TECH-1121 · 8.72 Impact Factor
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    Dataset: Ning JOP

  • Cancer Research 08/2015; 75(15 Supplement):4223-4223. DOI:10.1158/1538-7445.AM2015-4223 · 9.33 Impact Factor
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    ABSTRACT: Human papilloma virus (HPV) infection causes cancers and their precursors (high-grade squamous intraepithelial lesions) near cervical and anal squamocolumnar junctions. Recently described cervical squamocolumnar junction cells are putative residual embryonic cells near the cervical transformation zone. These cells appear multipotential and share an identical immunophenotype (strongly CK7-positive) with over 90% of high-grade squamous intraepithelial lesions and cervical carcinomas. However, because the number of new cervical cancers discovered yearly world wide is 17-fold that of anal cancer, we posed the hypothesis that this difference in cancer risk reflects differences in the transition zones at the two sites. The microanatomy of the normal anal transformation zone (n=37) and topography and immunophenotype of anal squamous neoplasms (n=97) were studied. A discrete anal transition zone was composed of multilayered CK7-positive/p63-negative superficial columnar cells and an uninterrupted layer of CK7-negative/p63-positive basal cells. The CK7-negative/p63-positive basal cells were continuous with-and identical in appearance to-the basal cells of the mature squamous epithelium. This was in contrast to the cervical squamocolumnar junction, which harbored a single-layered CK7-positive/p63-negative squamocolumnar junction cell population. Of the 97 anal intraepithelial neoplasia/squamous cell carcinomas evaluated, only 27% (26/97) appeared to originate near the anal transition zone and only 23% (22/97) were CK7-positive. This study thus reveals two fundamental differences between the anus and the cervix: (1) the anal transition zone does not harbor a single monolayer of residual undifferentiated embryonic cells and (2) the dominant tumor immunophenotype is in keeping with an origin in metaplastic (CK7-negative) squamous rather than squamocolumnar junction (CK7-positive) epithelium. The implication is that, at birth, the embryonic cells in the anal transition zone have already begun to differentiate, presenting a metaplasia that-similar to vaginal and vulvar epithelium-is less prone to HPV-directed carcinogenesis. This in turn underscores the link between cancer risk and a very small and discrete population of vulnerable squamocolumnar junction cells in the cervix.Modern Pathology advance online publication, 15 May 2015; doi:10.1038/modpathol.2015.54.
    Modern Pathology 05/2015; 28(7). DOI:10.1038/modpathol.2015.54 · 6.19 Impact Factor
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    ABSTRACT: Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.
    Gastroenterology 04/2015; 148(4):S-729. DOI:10.1016/S0016-5085(15)32490-2 · 16.72 Impact Factor
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    ABSTRACT: Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to 1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analyzed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.
    The Journal of Pathology 03/2015; 236(3). DOI:10.1002/path.4533 · 7.43 Impact Factor
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    ABSTRACT: The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes. Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.
    Nature Cell Biology 03/2015; 17(4). DOI:10.1038/ncb3130 · 19.68 Impact Factor
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    ABSTRACT: The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynecologic tract and adult fallopian tube were Krt7p/ PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1) and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
    The Journal of Pathology 12/2014; 234(4). DOI:10.1002/path.4417 · 7.43 Impact Factor
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    ABSTRACT: Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASC(p63/Krt5), to this process. Here we show that pre-existing, intrinsically committed DASC(p63/Krt5) undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
    Nature 11/2014; 517(7536). DOI:10.1038/nature13903 · 41.46 Impact Factor
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    ABSTRACT: It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta catenin, EZH2 and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immuno-phenotypically distinct progeny under stromal influences via "top down" differentiation. Similarly, biphasic cell differentiation can be seen in the endometrium with a parallel in the juxtaposition of mesothelial and mullerian differentiation in the ovary. An abrupt mesothelial-Mullerian transition remains to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumor cells in HGSC and pinpointing where initial transformation and trans-differentiation occurs if the POSE is an origin. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.
    The Journal of Pathology 12/2013; 231(4). DOI:10.1002/path.4263 · 7.43 Impact Factor
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    ABSTRACT: Barrett's oesophagus is a premalignant condition, predisposing to oesophageal adenocarcinoma. However, some adenocarcinoma may arise in columnar lined oesophagus without goblet cells. Our aim was to evaluate the biological properties of non-goblet columnar lined oesophagus only and elucidate its relationship with Barrett's oesophagus and associated neoplasia. Endoscopic biopsies from patients with Barrett's oesophagus (n=30), non-goblet columnar lined oesophagus (n=14), Barrett's oesophagus associated high grade dysplasia (n=6) and adenocarcinoma (n=4) were selected. Immunostaining for villin, claudin 3 and MUC4 was performed. Statistical analysis was performed and a p value <0.05 was considered significant. Villin and MUC4 were positive in 42%, 100% each and 50% in non-goblet columnar lined oesophagus, Barrett's oesophagus, high grade dysplasia and adenocarcinoma respectively, while claudin 3 was 100% positive in all the groups. In non-goblet columnar lined oesophagus, six cases that were villin immunopositive, showed positive expression for claudin 3 and/or MUC4 and there was no difference from the high grade dysplasia or adenocarcinoma (p>0.05). Our results indicate that a subset of non-goblet columnar lined oesophagus shows an intestinal phenotype representing an early stage of Barrett's oesophagus. This subset probably harbours the potential to change into adenocarcinoma in the long term.
    Digestive and Liver Disease 11/2013; 46(2). DOI:10.1016/j.dld.2013.09.025 · 2.96 Impact Factor
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    ABSTRACT: Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Up-regulation of p63 expression is required for ASPP2(Δexon3/+) BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.
    Proceedings of the National Academy of Sciences 10/2013; 110(44). DOI:10.1073/pnas.1309362110 · 9.67 Impact Factor
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    ABSTRACT: Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.
    The American journal of surgical pathology 09/2013; 37(9):1311-8. DOI:10.1097/PAS.0b013e3182989ee2 · 5.15 Impact Factor
  • Wa Xian · Frank McKeon · Khek Yu Ho ·
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    ABSTRACT: The best means to improve gastrointestinal cancer survival is screening and treatment of the early lesions. In esophageal adenocarcinoma, there is increasing thought that low-grade dysplasia and perhaps even "high-risk" Barrett's esophagus represent the most attractive targets for achieving a cure. An issue with Barrett's esophagus is that endoscopy alone cannot distinguish Barrett's esophagus from columnar lined epithelium or from areas of low-grade dysplasia. Much effort has therefore been devoted to discover molecular biomarkers of "high-risk" states and develop imaging tools for detecting these biomarkers in a manner that could assist the real-time in-vivo targeting of sites for biopsy. The strategy we have employed is to generate stem cell clones from Barrett's esophagus biopsies and compare their gene expression profiles with patient-matched stem cell clones of the esophageal squamous epithelia and gastric cardia. It is anticipated that by mining the expression datasets of these Barrett's stem cell clones, we will be able to identify unique cell surface markers of the Barrett's stem cells against which cytotoxic antibodies or aptamers can be developed, and used to aid the endoscopist in identifying regions of atypia for biopsy, making real-time diagnosis, stratifying patients during the examination, and ultimately directing therapy in a preemptive manner. This review will focus on Barrett's esophagus and its associated neoplasia to illustrate the utility of biomarker and molecular imaging in aiding targeted biopsy, making real-time diagnosis, stratifying lesions during examination, and directing treatment of this gastrointestinal disorder during surveillance endoscopy.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 08/2013; 12(1). DOI:10.1016/j.cgh.2013.08.033 · 7.90 Impact Factor
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    Cancer Research 08/2013; 73(8 Supplement):4791-4791. DOI:10.1158/1538-7445.AM2013-4791 · 9.33 Impact Factor
  • C. Crum · G. Ning · M. Herfs · Y. Yamamoto · F. McKeon · W. Xian ·

    Gynecologic Oncology 07/2013; 130(1):e24-e25. DOI:10.1016/j.ygyno.2013.04.119 · 3.77 Impact Factor
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    ABSTRACT: Serous tubal intraepithelial carcinoma (STIC) is a noninvasive phase of pelvic serous cancer at risk for metastasizing. Because of its biologic significance, its accurate distinction from nonmalignant mimics is important. Loss of cell orientation is an important feature of STIC. We sought to determine whether the immunohistochemical localization of cytoskeletal-organizing proteins phospho-ezrin-radaxin-moesin (p-ERM) would be useful in making this distinction. The benign oviductal entities (normal and p53 signatures), premalignant atypias (tubal intraepithelial lesions in transition), serous intraepithelial carcinomas (STICs), and carcinomas were analyzed for 5 staining patterns and compared. Linear or uniform luminal p-ERM staining was strongly associated with benign mucosa in contrast to STICs, in which it was lost and often replaced by nonlinear or nonuniform patterns highlighting individually cell groups or single cells. Premalignant atypias were similar to benign mucosa by p-ERM staining and retained the linear luminal pattern. This study shows, for the first time, that patterns of staining for an immunohistochemical correlate of cell polarity (p-ERM) differ between STICs, their benign counterparts and premalignant atypias that do not fulfill the criteria for STICs. If confirmed, these findings warrant further analysis of indices of cell polarity as objective markers for the diagnosis and mapping of the evolution of pelvic serous precursors.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2013; 32(4). DOI:10.1097/PGP.0b013e31826feee2 · 1.67 Impact Factor
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    ABSTRACT: The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodeling and neoplasia is unclear. In the present study, we analyzed the SC junction immunophenotype during pre and postnatal human and mouse development and in the adult, processes of metaplastic evolution of SC junction, microglandular change and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the SC junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic/SC junction cells gave rise to subjacent metaplastic basal/reserve cells with a switch from the SC junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or "top down" differentiation. A similar pattern was noted in high grade squamous intraepithelial lesions (HSIL), suggesting HPV infection of the cuboidal SC junction cells initiated outgrowth of basally-oriented neoplastic progeny. The progressive loss of the embryonic/SC junction markers occurred with top-down differentiation during development, remodeling and early neoplasia. Interestingly, most low grade SILs were SC junction negative, implying infection of metaplastic progeny rather than the original SC junction cells. This proposed model of "top down" differentiation resolves the mystery of how SC junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the SC junction is uniquely susceptible to carcinogenic HPV infection. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 02/2013; 229(3). DOI:10.1002/path.4110 · 7.43 Impact Factor

Publication Stats

19k Citations
1,810.63 Total Impact Points


  • 2013-2015
    • The Jackson Laboratory
      BHB, Maine, United States
    • University of Connecticut
      • Department of Genetics and Developmental Biology
      Storrs, Connecticut, United States
  • 2011-2015
    • Genome Institute of Singapore
      • Department of Stem Cell and Developmental Biology
      Tumasik, Singapore
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1999-2013
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 1970-2013
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
  • 2001-2012
    • Brigham and Women's Hospital
      • • Division of Women's and Perinatal Pathology
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2007
    • Nagoya University
      Nagoya, Aichi, Japan
  • 2003
    • Pohang University of Science and Technology
      • Division of Molecular and Life Sciences
      Andong, North Gyeongsang, South Korea
    • University of Oregon
      • Department of Biology
      Eugene, Oregon, United States
  • 2002
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1993
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1988
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
  • 1983
    • University of California, San Francisco
      • Department of Dermatology
      San Francisco, California, United States