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In future, human cell cultures will provide the tools for tissue engineering, gene therapy and the understanding of protein function. The chapters in these volumes are written by leading experts in each field to provide a resource for everyone who works with human cells in the laboratory. John Masters and Bernhard Palsson vii This page intentionally left blank.


Introduction Continuous cell lines derived from human cancers are the most widely used resource in laboratory-based cancer research. The first 3 volumes of this series on Human Cell Culture are devoted to these cancer cell lines. The chapters in these first 3 volumes have a common aim. Their purpose is to address 3 questions of fundamental importance to the relevance of human cancer cell lines as model systems of each type of cancer: 1. Do the cell lines available accurately represent the clinical presentation?

Do the cell lines accurately represent the histopathology of the original tumors? Do the cell lines accurately represent the molecular genetics of this type of cancer? The cancer cell lines available are derived, in most cases, from the more aggressive and advanced cancers. There are few cell lines derived from low grade organ-confined cancers. This gap can be filled with conditionally immortalized human cancer cell lines. We do not know why the success rate for establishing cell lines is so low for some types of cancer and so high for others.

The histopathology of the tumor of origin and the extent to which the derived cell line retains the differentiated features of that tumor are critical. It is essential that representative cell lines are selected for study, and it is hoped that the chapters in these volumes will help appropriate selections to be made. The data on the molecular genetics of cancer cell lines has been difficult to gather as it is widely distributed throughout the literature and in a stage of transition.

We do not yet know the identity of many of the altered genes for each type of cancer, or what their individual roles are in the progression of the disease. Despite being an essential resource for much of cancer research, established cell lines are associated with problems that are often ignored, but which can invalidate the work.

The most important problems are cross- ix x Introduction contamination between cells of either the same or different species, contamination with microorganisms usually Mycoplasma and phenotypic and genotypic drift. Both cross-contamination and the presence of Mycoplasma are easily checked by PCR-based methods. Phenotypic and genotypic drift can be avoided by good tissue culture practice, ie by growing cells for only short periods before returning to frozen stocks.

Many cell lines are cross-contaminated with other human or animal cell lines. Despite the fact that cell lines called Chang liver, KB and Hep-2 are known to be HeLa, authors often fail to acknowledge the fact. HeLa is just the tip of the iceberg of cell line cross-contamination.

For most cell lines there is no proof of origin from a particular individual or tumor by a reliable method DNA fingerprinting is recommended. Mycoplasma contamination is a widespread and recurring problem. Laboratories that do not test for Mycoplasma contamination often have it, and consequently allow it to spread unchecked. How many putative novel human cancer-associated proteins are derived from Mycoplasma?

Many human cancer cell lines are easy to grow and maintain. With simple precautions and good practice they can provide models that are representative of almost every type of clinically advanced human cancer. Many more cell lines are needed to represent low grade, clinically localized cancer. Chapter 1 Sarcomas Beverly A. Tel: ; Fax: Innumerable attempts were made to obtain continuous growth of tumor cells derived from surgical specimens in well-defined culture systems by varying the nutrient media, serum, growth factors and hormones and substrata glass, plastic, suspension, cellular feeder-layer.

Most of these attempts failed to produce immortal tumor cell lines; however, those that succeeded resulted in the development of the vast majority of the human tumor cell lines that are in use in cancer research today Bloom ; Giard et al. After passage for generations in animals, cell culture lines were developed from some of these Hazelton et al.

Much of the research on the biochemistry and molecular biology of cancer has been derived from these cell lines, although it may certainly be questioned whether the few cells from which immortal cell culture lines originated are representative of their diseases of origin. It was recognized early on that some tissue types adapted to growth in cell culture more readily than others.

Sarcomas were among the more readily cell culture-adapted cell types, so that most of the widely used cell lines in the sarcoma family have been carried in culture for 20 to 25 years. Tables list 54 human sarcoma cell lines including: 4 fibrosarcoma; 13 rhabdomyosarcoma; 26 osteosarcoma; 3 leiomyosarcoma; 1 synovial sarcoma; 3 liposarcoma and 4 chondrosarcoma. W Masters and B. Palsson eds. Printed in Great Britain. Specimen site lung met. The HT cell line was initiated from a biopsy of a fibrosarcoma arising adjacent to the acetabulum of a 35 year old male in July Rasheed et al. The patient had never received chemotherapy or radiation therapy.

The primary tumor biopsy was very cellular with little intercellular material and invaded the acetabulum cartilage Rasheed et al. Although the major cell type in the tumor was an elongated tumor cell with only a minor population of rounded cells, the HT cell line that was developed consisted almost entirely of rounded cells. The doubling time of the cell line was 26 hours Rasheed et al. The human fibrosarcoma cell line HT has been used extensively to study the effect of anti-inflammatory agents such as glucocorticoids on the gene expression of inflammatory mediators Andreasen et al.

The human fibrosarcoma cell line HT has also been used extensively in the study of the extracellular matrix proteins involved in attachment, invasion and metastasis Nurcombe et al. Human HT fibrosarcoma cells have been instrumental in examining the role of the ras-oncogenes in the transformed phenotype Lowe and Goeddel ; Paterson et al. It was found that human HT fibrosarcoma cells readily accept transfected genes carried by a variety of vectors, therefore this cell line has been useful in the study of gene overexpression and potential gene therapy strategies Nagy and Baker ; Tang et al.

The human HT fibrosarcoma cell line has also been useful in the study of therapy related issues in the treatment of fibrosarcoma Falugi et al. Teicher 12 2. The RD cell line was established from a malignant embryonal rhabdomyosarcoma of the pelvis of a 7-year-old female in McAllister et al. It has been used to examine the potential of differentiating agents as a cancer therapy Aguanno et al. The RD cell line has also been used extensively in the study of adhesion molecules, cytopathic effects and matrix components Chan et al.

In , Houghton and colleagues reported the initiation of a continuing effort on the growth and characterization of childhood rhabdomyosarcoma as xenografts in immune-deprived female mice. Eleven surgical specimens of rhabdomyosarcoma, 2 bone marrow samples and 1 sample of cells from ascitic fluid were implanted in immunodeficient animals and seven xenografts were obtained. The xenografts retained the histological characteristics of the tumors.

The rhabdomyosarcoma xenograft lines established by Houghton have been used extensively in the development of new therapeutic approaches to this disease Houghton et al. The human Rh28 rhabdomyosarcoma cell line has been characterized morphologically and molecularly Shapiro et al. The Rh28 cell line displayed a constant population doubling time hrs until passage 60 when proliferation gradually ceased.

The loss of proliferative capacity was associated with morphological evidence of differentiation into multinucleated myotubes, fusion and the expression of numerous musclespecific genes. Subsequently, six human Rh rhabdomyosarcoma cell lines were analyzed for myogenic regulatory protein MyoD 1 expression Dias et al. In , McAllister et al.

No neural or glial elements were demonstrated in the cultured cells by electron microscopy. However, in , Stratton et al. Based on this finding and on the phenotypic characteristics of the TE cells such as the presence of Sarcomas 13 muscle-type nicotinic acetylcholine receptors and the intermediate filament protein desmin the identity of the line was further investigated. Cytogenetic analysis and DNA fingerprinting at several loci established that the TE cell line and the RD cell line were derivatives of the same cell line.

This study established TE as a rhabdomyosarcoma. A drug resistant subline of TE TEMR has been developed and its response to several drugs has been compared with that of the parent TE 1 rhabdomyosarcoma Castellino et al. In three cell lines isolated from the same osteosarcoma patient before treatment HTLA , after chemotherapy HTLA and from a lung metastasis HTLA , it was found that the c-myc protooncogene was amplified and that the overexpression of c-myc in cell culture and in xenografts was not different among the three cell lines Bogenmann et al.

Asano and Yamashita assessed the expression of oncogenes in ten human osteosarcoma cell lines grown as xenografts in nude mice. Five of the cell lines overexpressed c-myc; four of the lines overexpressed c-Ha-ras and one line overexpressed cfos. Transfection of the human TE85 osteogenic sarcoma cell line with the c-Ha-ras gene also conferred tumorigenicity on this line Fidler et al.

Transformation of the human osteosarcoma cell line TE with the v-Ki-ras oncogene to form the subline KRIB resulted in a cell line that was tumorigenic and metastatic from an implant into the tibia Berlin et al. Transfection of the human Saos-2 osteosarcoma cell line with the retinoblastoma Rb tumor suppressor gene resulted in a subline which continued to proliferate but more slowly than the parent line and formed tumors but with a longer latency period than the parent line Zhou et al. On the other hand, transfection of human Saos-2 osteosarcoma cells with Bmyb stimulated DNA synthesis in growth-arrested cultures Sala et al.

Osteosarcoma cells are highly responsive to growth factors and cytokines. However, when the human OHA osteosarcoma cell line was continuously exposed to interferon-alpha after several passages there was an inhibition of cell proliferation Brouty-Boye et al. Interferon-gamma was a potent inhibitor of DNA synthesis in human Saos-2 osteosarcoma cells. Exposure to interferongamma and to a much lesser extent exposure to interferon-beta induced an increased expression of class II HLA antigens Katayama and Hanazawa ; Scotlandi et al. MG cells alone induce platelet aggregation; U-2OS cells induce platelet aggregation only after incubation of platelets with low concentrations of epinephrine Mehta et al.

Nuclear androgen receptor and its upregulation by dihydrotestosterone were observed in human MG osteosarcoma cells Etienne et al. Human osteosarcoma cells have been found to express angiogenic factors including vascular endothelial growth factor VEGF in MG cells as well as the angiogenesis inhibitor thrombospondin in MG cells and TE cells Clezardin et al. Bone alkaline phosphatase produced in osteoblastic cells plays a key role in the formation and calcification of the skeleton.

The expression of alkaline phosphatase orthophosphoric-monoester phosphohydrolase [alkaline optimum], EC 3. The alkaline phosphatase activity in MG cells is very low 0. Exposure of MG cells or Hu09 cells to vitamin D or analogs of vitamin D induced the synthesis of osteocalcin and alkaline phosphatase activity in these cells Kawai ; Valaja et al.

Sarcomas 15 These cell lines have been used widely to assess therapeutic approaches in osteosarcoma Tsang et al. Leiomyosarcomas of the retroperitoneum and the vena cava occur most commonly in women. Cutaneous and subcutaneous leiomyosarcomas generally affect men. Synovial sarcomas are most often composed of uniform small cells and most frequently occur in the extremities. Liposarcomas are the most commonly encountered soft-tissue tumors. The pleomorphic or poorly differentiated liposarcomas are characterized by pleomorphism, frequent mitosis, which may contain lipid droplets, and bizarre giant cells, which may appear as lipoblastic tissue.

The human HS liposarcoma cell. The HS cell line has been compared with the human HT fibrosarcoma cell line and the human Saos-2 osteosarcoma cell line with respect to retinoblastoma tumor suppressor gene status Rb and response to the antitumor antimetabolite drugs methotrexate and 5-fluorodeoxyuridine. Growth inhibition assays indicated that the IC50 values for methotrexate and 5-fluorodeoxyuridine in HS- 18, a liposarcoma cell line lacking retinoblastoma protein pRb and Saos-2, an osteosarcoma cell line with a truncated and nonfunctional pRb, were to fold and 4- to 1 1-fold higher respectively, than for the HT fibrosarcoma cell line, which has wild-type pRb.

In contrast, there was no significant difference in growth inhibition among these cell lines for the non-antimetabolites VP, cisplatin and doxorubicin. These results suggest the Rb gene product pRb may be involved in the mechanisms of interaction between cytotoxic agents and genes involved in cell cycle progression. Electron microscopically, the cells in the nodules resembled chondrocytes in vivo, but each cell had an irregular shaped nucleus which is a characteristic of tumor cells. The human KC chondrosarcoma cell line synthesizes keratan sulfate and produces chondrocytic large-aggregating proteoglycans.

The majority of the cell lines described herein were developed 20 to 30 years ago. More recently, laboratories have developed cell lines of a particular histology or with other specific properties of interest to that laboratory. These cell lines represent an enormous resource to the cancer research community and most are representative of the tumor of origin. Sarcomas References Aaronsen Exp Cell Res 1. Aguanno, A. Bouche, et al. Cancer Res Andreasen, P. Neilsen, et al. J Biol Chem Pyke, et al. Mol Cell Biol7 : Andress, D.

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Samid, et al. Billiau, A. Edy, et al. Antimicro Agents Chemother Block, J. Inerot, et al. J Bone Joint Surg 73A: Bloom, E. Bogenmann, E. Moghadam, et al. Brouty-Boye, D. Wybier-Franqui, et al. J Interferon Res 6: Butler, D. Scallon, et al. Cytokine 6: Cajot, J. Bamat, et al. Carloni, G. Venaut, et al. Castellino, S. Friedman, et al. Br J Cancer Chan, B.

Matsuura, et al. Science Cho Clezardin, P. Serre, et al. Dias, P. Parham, et al. Am J Pathol Dilling, M. Dias, et al. Douglas, E. Cell Genet. Espy, M. Wold, et al. J Clin Microbiol Etienne, M. Fischel, et al. Eur J Cancer Falugi, C. Castellani, et al. Basic Appl Histochem Farley, J. Kyeyune-Nyombi, et al. Clin Chem Fidler, I. Li, et al. Anticancer Res Fogh, J. Human tumor cells in vitro. New York, Plenum Press: Fogh et al. JNCI Wright et al. Fostad, O. Brogger, et al. Int J Cancer Fournier, B.

Ferralli, et al. J Endocrin Price J Cell Biol Garvin, A.

Stanley, et al. Am J Pathology Germani, A. Fusco, et al. Giard, D. Aaronson, et al. Goto, H. Matusi-Yuasa, et al. Arch Biochem Biophys Graves, D. Owen, et al. Hazelton, B. Houghton, et al. Hochhauser, D. Schnieders, et al. JNCZ Hodgkiss, R. Stratford Int J Radiat Biol Hoglund, M.

Siden, et al. Gene Horton, J. Thimmaiah, et al. Biochem Pharmacol Houghton, J. Meyer, et al. Cancer Treat Rep Williams, et al. Cheshire, et al. Houghton, P. Cancer Chemother Pharmacol Anticancer Drug Des 2: Shapiro, et al. Pediatr Clin North Am Tharp, et al. Iizuka, M. Yamauchi, et al. Iwasaki, H. Kukuchi, et al. Cancer Johnston, S. Diagn Microbiol Infect Dis Katayama, H.

Hanazawa Meika Daigaku Shi Zass Kawai, A. Clin Orthop Kawai, K. Kamatani, et al. Journal of Biological Chemistry Kelland, L. Bingle, et al. Kim, N. Sekine, et al. J Biochem Kinsey, B. Van den Abbeele, et al. Kjonniksen, I. Winderen, et al. Kubota, S. Fridman, et al. Mitsudomi, et al. Larsen, R. Bruland, et al. Li, W.

Cancer Cell Lines, Part 1

Fan, et al. Lindberg, A. Crowell, et al. Virus Res Lollini, P. DeGiovanni, et al. Invasion and Metastasis Lowe, D. Goeddel Mol Cell Biol7: Manonen, A. Maenpaa Marini, F. Cannon, et al. Hum Gene Ther 6: Masurel, D. McAllister, R. Gardner, et al.

Issacs, et al. Melnyk, et al. Nat New Biol Medcalf, R. Richards, et al. EMBO J 5: Mehta, P. Lawson, et al. Mukaida, H. Huabayashi, et al. International Journal of Cancer Mukaida, N. Gussella, et al. Immunology Myohanen, H. Stephens, et al. J Histochem Cytochem Nagy, A. Baker J Cell Sci Nakamura, T. Nakamura, et al. Nardeaux, P. Daya-Grosgean, et al. Neilsen, L. Andreasen, et al. Thromb Haemost Nielsen, L. Lecander, et al. Thromb Res Noel, A. Borcy, et al. Anticancer Res 1. Nurcombe, V.

Aumailley, et al. Eur J Biochem 9. Oikarinen, A. Hoyhtya, et al. Arch Dermatol Res Palmer, H. Maher, et al. In Wtro Cell Dev Biol Paterson, H. Reeves, et al.

Complete Cell Line List - MI Bioresearch

Cell Peebles, P. Trisch, et al. Pediatric Res Pontbriant, C. Chen, et al. J Cell Physiol Ponten, J. Saksela Int J Cancer 2: Raile, K. Holfich, et al. Rani, A. Qu, et al. Carcinogenesis Sarcomas Rasheed, S. Nelson-Rees, et al. Rathod, R. Kharti Rhim, J. Cho, et al. Park, et al. Nature 75 1. Richter, M. Graves Romano, J. Ehrhart, et al. Oncogene 4: Sakayama, K.

Masuno, et al. Biochem J Sala, A. Cassella, et al. Samid, D. Clin Biol 1: Sanchez, A. Chesterman, et al. Scotlandi, K. Baldini, et al. Shapiro, D. Shaughnessey, E.

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Walker, et al. Slovak, M. Mirski, et al. Sonoda, J. Hibasami, et al. Stephens, R. Pollanen, et al. Stratton, M. Darling, et al. Suarez, H. Grosjeachn, et al. Characterization of a human osteosarcoma oncogene. Retroviruses and Human Pathology. Gallo, D. Stehelin and 0. Clifton, NJ, Humana Press. Supino, R. Bardella, et al. Tumori Takashi Takigawa, M. Pan, et al. Tajima, et al. Tang, E, P. J Hisrochem Cytochem Tanimoto, K. Tamura, et al. Tsang, K. Warren, et al. Tsuchiya, H. Tomita Gan To Kagaku Ryoho Ueda, E.

Ohno, et al. Valaja, T. Mahonen, et al. Walker, M. Lim, et al. Watanabe, H. Carmi, et al. Weich, H.

Cancer Cell Lines Part 1

Sebald, et al. Yamada, K. Kennedy, et al. Zhou, Y. PNAS Zhuang, Y. Blauer, et al. J Steroid Biochem Mol Biol Zwelling, L. Slovak, et al. Chapter 2 Neuroblastoma Carol J. This results in an annual incidence of approximately 1 in , children less than 15 years of age world-wide. Some studies indicate a bimodal age distribution with one peak at approximately 1 year and the second between 2 and 4 years 1,2. In children under 5 years of age, neuroblastoma usually presents in the abdominal region involving the sympathetic ganglia of the paraspinal region or the adrenal gland.

In infants under a year of age there is a higher incidence of tumors in the thoracic region. In Stage I and II neuroblastoma NB where tumor is confined to the originating organ or surrounding tissue, the prognosis is favorable. Of all human tumors neuroblastomas have one of the highest rates of spontaneous tumor regression. This is primarily due to an unusual type of neuroblastoma called Stage IVS that occurs in infants under a year of age who present with widely disseminated disease that typically resolves with minimal therapy.

Stage IVS tumors have intrigued scientists studying neuroblastoma who feel that an understanding of this disease entity will provide clues to the more devastating presentations of neuroblastoma. This model proposed that all NB derive from a single cell that is transformed from a normal cell by two mutations; one that may arise prezygotically in the germline and the second that arises in a somatic cell of the target tissue.

This "two-hit" model of tumor development was hypothesized to describe the genetics of retinoblastoma tumors and subsequently was verified with the identification of Rb, the retinoblastoma tumor suppressor gene 4. While the probability of tumor occurrence would be high in familial or germline cases of neuroblastoma, the actual incidence is quite low. This low incidence may be due to the fact that the elaboration of both mutations causes an embryonic lethal condition or that there is a failure to detect affected parents because they have occult tumors that spontaneously regress or benign tumor forms such as ganglioneuromas 5,6.

The majority of neuroblastoma arise sporadically and as such germline mutations would not occur and both mutations would arise somatically. Neuroblastomas occur early in life and the age-associated incidence suggests that the target cell may differentiate or does not persist into adult life. For sporadic neuroblastomas to occur, both mutations must occur in a cell before it fully differentiates.

The long term culture of neuroblastoma tumors and the differentiated properties these cells express in culture have fascinated investigators who study these cultures in order to understand the propensity of neuroblastoma cells to differentiate in vivo and in vitro 8. Tumor tissue can be obtained from primary tumor samples obtained from surgical resections, fine needle and bone marrow aspirates and occasionally from peripheral blood. Frequently fibroblasts grow out of these preparations. However, if the tumor sample is cultured on extracellular matrix components such as laminin or collagen the growth of fibroblasts may be reduced.

Bone marrow samples should be aspirated into a preservative-free heparinized syringe. Techniques for the isolation of the tumor Neuroblastoma 23 cells from marrow cells have varied from direct culture C to density gradient centrifugation DG. In the direct culture method, bone marrow is diluted into media and red blood cells are washed off during in vitro culture. Red blood cells may be separated from tumor cells by placing the diluted bone marrow sample on a ficoll-hypaque gradient density 1.

The interface layer containing the tumor cells and normal bone marrow cells is collected and washed several times before it is cultured in complete media. Cultures should be observed several times a week over the first few weeks and the media replenished every few days. Many neuroblastoma tumor cells will attach to the culture dish.

However, tumor spheroids may remain in suspension and thus the spent media may contain non-adherent tumor cells and should be centrifuged and the pelleted cells re-cultured in a separate flask. After washing detached cells in media, cells may be resuspended in fresh media in multiple or larger tissue culture flasks. The use of antibiotics minimizes the possibility of microbial contamination during the initial phase of culture, however long-term use in established cultures can lead to occult contamination.

Primary neuroblastoma cells in culture may be small, rounded or tear shaped cells with a relatively immature appearance, although cells frequently elaborate long neurite-like processes. NB cells may grow in cell aggregates that are only loosely substrate-adherent. The morphological appearance of established neuroblastoma cell lines varies see Biological features with cells having a neuroblastic, intermediate and substrate-adherent or flat morphology 9, Cultures may be homogeneous or heterogeneous for these cell types.

Reports of the adaptation of neuroblastoma cell lines to serum-free conditions in the absence of additional growth factors have been infrequent. Table 1 lists the clinical features from which over neuroblastoma cell lines have been derived. These cytogenetic features are most commonly found in advanced stage tumors and most neuroblastoma cell lines are derived from advanced stage tumors Table 2 and 2A.

Houghton " " " 89 90 91 92 Ref. Primary site adrenal retroperit. Patient yr. Continued on next page 4 4 4 unk. Continued on next page 4 4 4 4 3 3 3 3 unk. Houghton, pc der 17 t 17;? This implies that several putative tumor suppressor genes are located on chromosome 1p. In neuroblastoma, chromosome 1p deletions are the most consistent nonrandom genetic alteration and result in chromosome 1p monosomy. The deletion is variable in neuroblastoma but consistently encompassing 1p At least two putative suppressor genes have been proposed to reside in this region as deletions can be grouped into those whose deletion encompasses 1p Recently a candidate tumor suppressor gene p73 has been identified that maps to 1p Although the p73 gene is an attractive candidate NB tumor suppressor gene as it has structural and functional homologies to p53, it is not typically altered in NB tumors or cell lines.

It is not known if the failure to express p73 is due to imprinting of the remaining p73 allele. Some neuroblastomas such as IMR however do express p73 MycN maps to 2p and is the common gene contained in the double minute chromosomes DMs and homogeneous staining regions HSRs that characterize a subset of NB tumors that have a particularly poor prognosis 1 8.

The size of the amplicon varies and other genes found in the amplicon include ornithine decarboxylase, and DDX, a DEAD box protein encoding gene This lead to the hypothesis that DMs were derived from HSRs and were different manifestations of the same underlying genetic alteration The variable number of DMs in tumor cells results from the varying distribution of DMs during cytokinesis. A recent report suggests that only 1 of the possibly 2 tumor suppressor genes localized to 1p is associated with amplification of N-myc A recent study using comparative genomic hybridization identified that chromosome 17 gain occurred in a high percentage of cases, in Stage 1 and 2 and even 4S suggesting that alterations in this region may be one of the early events involved in NB tumorigenesis Chromosome 17 has tumor suppressor activity in NB cells 23 and mutations and amplification of nm23, a gene on chromosome 17q21 that has a metastasis suppressing ability on some tumor cell types, are detected in poor prognosis patients Typically these genetic alterations have been detected in advanced stage neuroblastomas and derived cell lines and rarely in tumors from low stage disease.

The prevalence of LOH or mutations in NF1 has not been thoroughly analyzed, although there is a recent report of a neuroblastoma patient with a homozygous deletion in NF1 Translocations and alterations of the region near NF1 on 17q have been described Although a mutation at codon 59 in N-ras was detected in a subline of SK-N-SH, it was different from the codon 61 mutation detected in the original transforming N-ras.

This suggests that the mutation in N-ras was not present in the primary tumor and was probably acquired during in vitro culture 3. The neural crest is a transitory structure that arises during the closure of the neural tube. Neural crest cells migrate ventrally and laterally to contribute to a variety of tissues including the peripheral nervous system, medullary cells of the adrenal gland, calcitonin producing cells of thyroid, pigmented cells, and mesectodermal derivatives.

Growth and differentiation specific peptides encountered by migratory neural crest cells are thought to influence their development and lineage specific differentiation. The histopathologic appearance of neuroblastoma represents a spectrum from sheets of monomorphic undifferentiated, small, round blue cells to nests of neuroblasts surrounded by fibrillar bundles to differentiated ganglionic cells. These histologic subtypes correspond to neuroblastoma, ganglioneuroblastoma and ganglioneuroma, respectively.

Immunohistochemical stains for neurofilaments, synaptophysin and neuron-specific enolase have been utilized to distinguish it from other small round blue cell tumors of childhood. Ganglioneuroblastoma is a heterogeneous group in which tumors contain the spectrum of immature to fully differentiated cells and some stromal component. Ganglioneuroma is composed of mature ganglion cells, neuropil and Schwann cells.

Recent evidence indicates that the Schwannian component of these tumors represents an infiltrate of normal cells rather than the differentiation of the tumor cells into Schwannian cells Shimada and colleagues have developed a classification system based on histopathologic features and age which has prognostic utility In this system the presence or absence of Schwann cell stroma; the degree of differentiation and the mitosis-karyorrhexis index MKI were considered in addition to age at diagnosis.

Favorable histology associated with a good prognosis is: stroma rich without a nodular pattern in any age group; or stroma poor histology in ages 1. One of the hallmarks of NB cells in culture is their spontaneous or induced elaboration of neuritic processes. Other neuronal properties include; the synthesis of neurotransmitter biosynthetic enzymes; expression of neurofilaments; opioid, muscarinic and neurotrophin receptor expression; dense core granules, which are the presumed sites of catecholamine storage; immunoreactivity to neuron specific enolase.

There are few lineage specific markers discriminating neuronal from neuroendocrine cell types. Most neuroblastoma cell lines are derived from tumor tissue of patients with advanced stage disease. However, these lines contain 1pdel and N-myc amplification and the patients from whom these cell lines were derived eventually died. While CLB-Pe is derived from a stage I neuroblastoma, the patient relapsed rapidly with metastasis to the bone marrow and consequently may not be representative of tissue derived from a stage I tumor Many established neuroblastoma cell lines contain at least 3 morphological variants that contribute to the heterogeneity in these cell lines; neuroblastic N , flat or substrate adherent S and intermediate I cell types 10,44, Morphologic subtypes from a number of neuroblastoma cell lines have been cloned Table 4 and also can be distinguished by characteristic biochemical markers.

Some clonal populations have the capacity to spontaneously interconvert or transdifferentiate from one morphologic type to another. It is thought that this heterogeneity may reflect their derivation from multi-potent neural crest precursors. N-type and I-type cells express neurofilament proteins while I-type and S-type cells are more strongly positive for vimentin than N-type cells. Rather than focus on how to resolve the problem of HeLa cell contamination, many scientists and science writers continue to document this problem as simply a contamination issue — caused not by human error or shortcomings but by the hardiness, proliferating, or overpowering nature of HeLa.

Regrettably, cross-contamination and misidentification are still common within the research community. Many cell lines were cross-contaminated during establishment; this means that all work using those cell lines has incorrectly used the contaminant — which may come from a different species or a different tissue. A cell line is considered to be misidentified if it no longer corresponds to the individual from whom it was first established.

Many cases of misidentification are caused by cross-contamination, where another, faster growing, cell line is introduced into that culture. HeLa was described by Leigh Van Valen as an example of the contemporary creation of a new species, dubbed Helacyton gartleri , due to their ability to replicate indefinitely, and their non-human number of chromosomes.

The species was named after Stanley M. However, this proposal has not been taken seriously by other prominent evolutionary biologists, nor by scientists in other disciplines. Van Valen's argument of HeLa being a new species does not fulfill the criteria for an independent unicellular asexually reproducing species because of the notorious instability of HeLa's karyotype and their lack of a strict ancestral-descendant lineage.

Multiphoton fluorescence image of HeLa cells stained with the actin binding toxin phalloidin red , microtubules cyan and cell nuclei blue. The tubulin antibody shows the distribution of microtubules and the Ki antibody is expressed in cells about to divide. Preparation, antibodies and image courtesy of EnCor Biotechnology.

HeLa was the subject of a book by Rebecca Skloot , The Immortal Life of Henrietta Lacks , investigating the historical context of the cell line and how the Lacks family was involved its use. The movie is based on the book, of the same name, written by Rebecca Skloot. From Wikipedia, the free encyclopedia. For other uses, see Hela disambiguation. Leigh Van Valen. Scanning electron micrograph of just-divided HeLa cells. HeLa cells stained with Hoechst Viral multiplication in a stable strain of human malignant epithelial cells strain HeLa derived from an epidermoid carcinoma of the cervix".

Journal of Experimental Medicine. A list of cross-contaminated or misidentified cell lines". The Virginian-Pilot. Retrieved ABC World News. The Guardian. Retrieved 18 July J Exp Med published May 1, Baltimore City Paper. Archived from the original on August 14, Retrieved 2 March Bibcode : PNAS The New York Times. Retrieved 23 April A; Hutchins, G. M The Immortal Life of Henrietta Lacks. Seattle Times.

Berkeley Science Review. The Scientist. Nature Reviews Cancer. Journal of Health Care for the Poor and Underserved. Journal of the American Statistical Association. Journal of Virology. Virus Research. The Journal of Biological Chemistry. Journal of Cellular Physiology. Food Chemistry. Journal of Biomaterials China. Crit Care Med. Hulser Invasion Metastasis. Retrieved 3 April Bibcode : Sci Archives of Iranian Medicine. Cancer Res. G3: Genes, Genomes, Genetics.

Cell Biol. Burton; Jacob O. Kitzman; Joseph B. Hiatt; Alexandra P. Lewis; Beth K. Nature published August 8, Bibcode : Natur. Retrieved 8 August The National Institutes of Health. August 7, BMC Genomics.