A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer

Herfs, Michaël; Yamamoto, Yusuke; Laury, Anna; Wang, Xia; Nucci, Marisa R.; McLaughlin-Drubin, Margaret E.; Münger, Karl; Feldman, Sarah; McKeon, Frank; Xian, Wa; Crum, Christopher P.

doi:10.1073/pnas.1202684109

Cited by 370 publications

(323 citation statements)

References 26 publications

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“…In particular, we provide evidence for a so far unappreciated lymphatic niche under the transformation zone considered as the site where neoplastic changes occur primarily during the cervical oncogenic process. 26,27 Furthermore, our study demonstrates that a global stromal evaluation sheds light on topographical features of the lymphatic vascular network that are worth considering in cervical cancer as well as other cancers.…”

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confidence: 99%

Improved computer-assisted analysis of the global lymphatic network in human cervical tissues

et al. 2014

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Lymphatic dissemination is a key event in cervical cancer progression and related tumor lymphatic markers are viewed as promising prognostic factor of nodal extension. However, validating such parameters requires an objective characterization of the lymphatic vasculature. Here, we performed a global analysis of the lymphatic network using a new computerized method applied on whole uterine cervical digital images. Sixty-eight cases of cervical neoplasia (12 CIN3, 10 FIGO stage 1A and 46 stage IB1) and 10 cases of normal cervical tissue were reacted with antibodies raised against D2-40, D2-40/p16 and D2-40/Ki67. Immunostained structures were automatically detected on whole slides. The lymphatic vessel density (D2-40), proliferating lymphatic vessel density (D2-40/ki67) and spatial lymphatic distribution in respect to the adjacent epithelium were assessed from normal cervix to early cervical cancer and correlated with lymphovascular space invasion and lymph node status. Prominent lymphatic vessel density and proliferating lymphatic vessel density are detected under the transformation zone of benign cervix and no further increase is noted during cancer progression. Notably, a shift of lymphatic vessel distribution toward the neoplastic edges is detected. In IB1 cervical cancer, although intra-and peritumoral lymphatic vessel density are neither correlated with lymphovascular space invasion nor with lymph node metastasis, a specific spatial distribution with more lymphatic vessels in the vicinity of tumor edges is predictive of lymphatic dissemination. Herein, we provide a new computerized method suitable for an innovative detailed analysis of the lymphatic network. We show that the transformation zone of the benign cervix acts as a baseline lymphangiogenic niche before the initiation of neoplastic process. During cancer progression, this specific microenvironment is maintained with lymphatic vessels even in closer vicinity to tumor cells.

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confidence: 99%

Improved computer-assisted analysis of the global lymphatic network in human cervical tissues

et al. 2014

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“…L'infection, à l'origine productive et asymptomatique, se transforme séquentiellement en une lésion bénigne, puis précancéreuse (dysplasie) ou cancéreuse (néoplasie) (Figure 1). Les génotypes HPV infectant l'épithé-lium cervical ne développeraient leur potentiel oncogène que dans certaines populations cellulaires de la jonction située entre l'exocol 2 et l'endocol [4], également le cas moins étudié du WHIM 3 , un syndrome d'immunodéficience très rare, dont un des signes cardinaux est une susceptibilité sélective aux infections par les HPV, se révélant dans plus de 70 % des cas par le développement de verrues cutanées étendues et de papillomes ano-génitaux qui évoluent en cancers [6]. 3 Le syndrome WHIM (Warts -hypogammaglobulinemiainfections -myelokathexis) est un déficit immunitaire autosomique dominant congénital principalement caractérisé par une lymphopénie, une neutropénie et une myélokathexie (présence anormalement élevée de neutrophiles matures dans la moelle osseuse) associées à une susceptibilité aux infections par les papillomavirus humains.…”

Section: Physiopathologie Des Papillomavirus Humains : Des Indices Apunclassified

“…Deux d'entre elles sont particulièrement sévères : l'atrophie microvillositaire (AMV) et la dysplasie épi-théliale intestinale (DEI en français, CTE pour congenital tufting enteropathy, en anglais) [3]. La DEI a été décrite pour la première fois en 1994 [4] et plus en détail en 1995 [5]. Cette entéropathie est moins fréquente que l'AMV, avec une incidence estimée à 1/200 000 en Europe.…”

Section: Nouvelleunclassified

La chimiokine CXCL12 et son récepteur CXCR4 dans le contrôle des infections par les papillomavirus humains

Meuris

Jaracz‐Ros

Gaudin³

et al. 2017

Med Sci (Paris)

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“…5 We have demonstrated previously that reserve cells arise from specialized columnar cells, including SC junction cells. [6][7][8] These cells in turn undergo squamous differentiation, and thus are ultimately responsible for the spectrum of squamous differentiation seen in the transformation zone. 8 The data support a decreasing risk of CIN3 development as these cells evolve from the cuboidal/low columnar cells in the SC junction to mature squamous epithelium, which could explain the much lower rate of CIN3 in the mature ectocervix, vagina and vulvar squamous epithelium.…”

Section: Dear Sirmentioning

confidence: 99%

Response to “Two major pathways of recurrent high‐grade squamous intraepithelial lesions of the cervix”

Herfs

Crum

2014

Intl Journal of Cancer

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The authors list two criticisms in their letter. 1 The first is that the follow-up period in this study was not long enough to appreciate potential new infections that could result in high grade cervical intraepithelial neoplasia (CIN) despite the presumed excision of the squamocolumnar (SC) junction. The second is that reserve cells are important progenitors of preinvasive squamous lesions of the cervix and because of their wider distribution they cannot be excised surgically.Concerning the first criticism, the authors describe studies from their institution that reported a recurrent CIN3 or adenocarcinoma in situ in less than 4 women per 1,000 treated by excision for CIN3 with negative margins, in contrast to 22% of those with positive margins. 2,3 Four recurrences per 1,000 cases of CIN3 is an impressively low recurrence rate given that CIN3 is usually a large lesion and the likelihood that some lesions might have been multifocal or were otherwise incompletely excised. In fact, this low rate could be seen as an argument for the potential value of SC junction excision in preventing CIN3. Would we not expect the risk of recurrent or new CIN3 to be higher if conization had not imposed a significant reduction in recurrence risk? Coupled with the fact that most recurrences are observed in the ectocervix, this is indirect evidence suggesting that excision of the SC junction significantly reduces risk of a "new" CIN3 within the cervix. As for the delayed presentation of some lesions, it is impossible to determine whether they were new or persistent lesions, in as much as details regarding location and HPV types are not provided in these studies. 2,3 In our discussion, we cite the paper by Kocken et al. which calculated the long-term risk of recurrence following excision. They also reported recurrences; however, when they maximized the likelihood of complete excision by both a negative cytology and HPV test, the rate of new or recurrent CIN3 was zero. 4 The second criticism was that subcolumnar reserve cellswhich cannot be completely excised because they can be found more cephalad in the endocervix-can be infected following excision and produce new lesions. Although we would never completely exclude this possibility, the data do not support isolated reserve cells as a major site of HPV infection. First, if this were the case we would expect the risk of new CIN3s to be higher following excision. Second, we would expect to find CIN3s associated with two entities in the cervix-endocervical polyps and microglandular change-that are replete with reserve cells. In fact, they are rare and uncommon sites of CIN3 development, respectively. Finally, if reserve cells were targeted, primary and recurrent CIN3s would be much more likely to be identified further up the endocervix away from the SC junction, which is not our experience or seen in our study. 5 We have demonstrated previously that reserve cells arise from specialized columnar cells, including SC junction cells. 6-8 These cells in turn undergo squamous differentiation,...

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A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer

Cited by 370 publications

References 26 publications

Improved computer-assisted analysis of the global lymphatic network in human cervical tissues

Improved computer-assisted analysis of the global lymphatic network in human cervical tissues

La chimiokine CXCL12 et son récepteur CXCR4 dans le contrôle des infections par les papillomavirus humains

Response to “Two major pathways of recurrent high‐grade squamous intraepithelial lesions of the cervix”

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