Thymidine Salvage Changes with Differentiation in Human Keratinocytes In Vitro

Schwartz, Pauline M.; Barnett, Steven K.; Reuveni, Haim

doi:10.1111/1523-1747.ep12492583

Cited by 17 publications

(6 citation statements)

References 21 publications

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“…Determining the proliferative state of the keratinocytes by DNA content using DNA dyes circumvents the problem of differential thymidine metabolism in normal and diseased keratinocytes. It has been shown that thymidine salvage and catabolism can be substantially different in proliferating versus differentiating cells in vitro (14). In addition, we found that psoriatic epidermis, relative to normal epidermis, demonstrates markedly increased thymidine phosphorylase activity (15), which could result in decreased incorporation of exogenous thymidine in psoriatic tissue.…”

Section: Discussionmentioning

confidence: 58%

“…In addition to quantitating cell size and cytoplasmic complexity, keratinocyte proliferation can be measured through the use of DNA dyes (13). DNA dyes circumvent the problem of cell metabolism of thymidine which can influence proliferative data acquired by radiolabded thymidine incorporation (14,15). Two groups of antigens are closely related to microanatomic location and stage of differentiation in the epidermis: adhesion molecules (16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and keratins (26)(27)(28)(29)(30)(31)(32).…”

mentioning

confidence: 99%

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Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis.

Bata-Csorgo

Hammerberg

Voorhees

et al. 1993

The Journal of Experimental Medicine

122

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SummaryIn this study we define the proliferative compartments of in vivo human epidermis, using specific antibodies related to cell differentiation (/31 and 84 integrins and K1/K10 differentiation keratins) and cell cycle (proliferating cell nuclear antigen [PCNA]) in combination with flow cytometric quantitation of the DNA content and optical characteristics of the cells. The B1 integrin (CD29) marked both of the potentially proliferative subsets in normal epidermis. One subset of normal epidermis is CD29+K1/K10 -, which was predominantly basal, and found to be comprised of slow cycling, small cells with primitive cytoplasmic organization. The vast majority (95.5%) of these cells were in a quiescent state (G0/early G1) as indicated by their lack of the cyclin, PCNA. The other proliferative subset of normal epidermis was CD29+K1/K10 +, which was suprabasal and occasional basal, highly proliferative, larger in size, and which exhibited a more complex cytoplasmic structure. Because early differentiation (K1/K10 expression) has begun in the CD29+K1/K10 + subset, it is highly likely that they represent the proliferative population which is capable of transiently amplifying itself before terminal differentiation. Within lesional psoriatic epidermis, similar proliferative cell populations were present as in normal epidermis, and the hyperproliferative defect was localized to the /31 and /34 integrin +, K1/K10-populations, which in normal epidermis is basally located and quiescent with regard to cell cycle. In psoriatic epidermis, a six-to sevenfold increase in the number of cells in the S/G2 + M phase of cell cycle was found among CD29+K1/K10 -cells (p <0.05). Furthermore, all lesional K1/K10-cells showed high PCNA positivity, indicating that all these cells had been recently induced into cell cycle. By contrast, the proportion of cycling cells among lesional psoriatic CD29+K1/K10 + keratinocytes was similar to normals. Anti-HLA-DR, CD45, and vimentin antibodies were used to concomitantly track the proliferative states of Langerhans cell, melanocyte, and infiltrating leukocyte populations. In normal epidermis, the cycling fractions (calls in S/G2/M phase) of these cells were similar to the CD29 § -keratinocytes, whereas in lesional epidermis their cycling pools were increased relative to normal, but not so much as the proliferative fractions of psoriatic CD29+K1/K10 -keratinocytes. These data demonstrate the use of simultaneous analysis of integrin expression, differentiation keratins, cyclin, cell cycle status, and optical characteristics of freshly isolated human epidermal cells. Such analysis allowed the physical identification and quantification of cycling populations in normal human skin, and has enabled the precise localization of the primary epidermal proliferative defect in psoriasis.

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis.

Bata-Csorgo

Hammerberg

Voorhees

et al. 1993

The Journal of Experimental Medicine

122

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“…Thus, similar to the increased production and accumulation of 5-FU in malignant cells due to their higher proliferation rate and increased TP activity, the higher proliferation rate of keratinocytes and associated TP activity compared to other normal somatic cells (non-friction ridge skin cells) has been suggested to preferentially expose keratinocytes to the local cytotoxicity of 5-FU metabolites (5). Furthermore, the interrelationship between proliferating keratinocytes and thymidine metabolism has been demonstrated by Schwartz et al (9). This suggests that, in addition to nuclear transcription errors caused by FUTP, in the absence of thymidine due to the inhibition of thymidylate synthase to form thymidylate, proper basal keratinocyte proliferation is inhibited thus supporting the histological findings of dyskeratosis and isolated basal keratinocyte necrobiosis (2–4) as well as the symptomatic desquamation associated with HFS previously noted.…”

Section: Introductionmentioning

confidence: 83%

“…The pathogenesis of capecitabine induced HFS is unknown (2, 4–5); however, evidence suggests that the same mechanism in which capecitabine prevents malignant cell growth is thought to be the cause of capecitabine induced HFS exhibiting its cytotoxic effects not only on malignant cells, but also on basal keratinocytes. TP has been found to also be expressed in a much higher concentration in friction ridge skin than other surrounding tissues (5) due to its association with keratinocyte hyperproliferation (9). Thus, similar to the increased production and accumulation of 5-FU in malignant cells due to their higher proliferation rate and increased TP activity, the higher proliferation rate of keratinocytes and associated TP activity compared to other normal somatic cells (non-friction ridge skin cells) has been suggested to preferentially expose keratinocytes to the local cytotoxicity of 5-FU metabolites (5).…”

Section: Introductionmentioning

confidence: 99%

Capecitabine-Induced Hand and Foot Syndrome and the Reproducibility of Friction Skin

Swofford

Schenck

2011

Academic Forensic Pathology

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In 2008 a sixty-two year old male was detained by United States Customs and Immigration officials when attempting to enter the United States because his fingerprints were not detectable thus preventing his identify from being verified. It was later reported by his physician in Singapore that the individual suffered from Hand and Foot Syndrome (palmar-plantar erythrodysaesthesia) as a result of his cancer treatment of capecitabine (N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine) which causes interruptions to the normal growth of keratinocytes in the friction skin. Capecitabine is a recently developed, orally administered fluoropyrimidine prodrug designed to generate 5-fluorouracil through a three step enzymatic process giving it antineoplastic properties to combat cancerous tumor growth in a number of different cancers, including adjuvant colon cancer, metastatic colorectal cancer, and metastatic breast cancer. This study consisted of a 253 day evaluation of the physiological effects to the friction ridge skin from an individual undergoing capecitabine chemotherapy treatment. The results indicate the quality of the friction ridge skin impressions decreased by 32% and to a degree which may impair the ability to positively identify individuals using friction skin impressions alone while undergoing this type of treatment and experiencing hand and foot syndrome. Following cessation of capecitabine treatment, normal growth of keratinocytes resumed returning the skin to a normal state with no indication of damage thus demonstrating the persistency of the friction ridge skin despite the temporary toxicity of capecitabine.

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“…(14), altered TP transcription may be related to the differentiation degree of the tumor and the BCC’s cell origin. TP immunoreactivity and TP enzymatic activity have already been correlated to the degree of differentiation of normal keratinocytes (13,14,43). Moreover, BCC cells share numerous biological and histological characteristics with keratinocytes located in the bulb of hair follicles and are held to derive from this follicular area (15), which constantly lacks TP immunoreactivity.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of thymidine phosphorylase/platelet‐derived endothelial cell growth factor in basal cell carcinomas

Stoebner

Gallic

Berthe

et al. 2008

Experimental Dermatology

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Thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor is associated with tumor angiogenesis. We evaluated the TP mRNA and protein expression in basal cell carcinomas (BCC) and in various skin tumors including numerous BCC histological simulants. Immunohistochemistry was performed on 99 paraffin sections of formalin-fixed skin tumors using monoclonal antibodies (mAb) against TP. TP mRNA levels were measured by real time RT-PCR in whole BCCs (wBCC) and laser capture microdissected (LCM) BCC tumor cells. TP immunostaining was negative in all BCC variants and in most of the benign trichogeneic tumors studied. By contrast, TP was constantly immunodetected in actinic keratosis (AK), squamous cell carcinomas (SCC), syringomatous carcinomas (SC), basosquamous carcinomas (BSC) and melanomas. TP mRNA levels were low and statistically not different in wBCC and normal skin but were strongly downregulated in LCM-BCC as compared with LCM-normal epidermis. We concluded that (i) anti-TP mAb is an useful marker to differentiate BCC from AK, SCC, BSC and SC but not from trichoblastic tumors, (ii) the lack of TP protein expression in BCC tumoral cells is linked to transcriptional regulatory mechanisms, (iii) the low TP mRNA levels in whole BCC may be related to the low intra-tumoral microvessel density, the slow growth and the very low metastatic potential of these tumors.

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Thymidine Salvage Changes with Differentiation in Human Keratinocytes In Vitro

Cited by 17 publications

References 21 publications

Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis.

Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis.

Capecitabine-Induced Hand and Foot Syndrome and the Reproducibility of Friction Skin

Decreased expression of thymidine phosphorylase/platelet‐derived endothelial cell growth factor in basal cell carcinomas

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