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Original Studies |
Dipartimento di Oncologia (L.F., L.E.P., G.F., R.G., F.B.), Istituto di Endocrinologia (F.P.), Dipartimento di Chirurgia (P.M.), Universita’ degli Studi di Pisa, Pisa, 56100, Italy; Laboratorio di Microbiologia, II Facolta’ di Medicina e Chirurgia Varese, Universita’ degli Studi di Pavia (R.C., A.T.), Varese, 21100, Italy; Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita’ degli Studi di Napoli (M.T.B.), Napoli, 80100, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Facolta’ di Medicina e Chirurgia di Catanzaro, Universita’ degli Studi di Reggio Calabria (A.F.), Catanzaro, 88100, Italy
Address all correspondence and requests for reprints to: Fulvio Basolo, M.D., Department of Oncology, University of Pisa, 57, Via Roma, 56126, Pisa, Italy.
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Abstract |
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, IL-1-ß, and IL-4 was observed. No
modulation of cell proliferation and DNA synthesis in FB-1 cells has
been observed after the addition of exogenous IL-6. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cultured cells and cell lines are a useful mean to study the molecular event and regulatory mechanism of cell growth and also the neoplastic progression of this type of cancer. Because few cell lines derived from anaplastic carcinomas have been reported in literature, we recently established and widely characterized a new cell line, FB-1, derived from an undifferentiated carcinoma. In this report, we analyze the morphologic feature, immunophenotypic characteristics, and the kariotype of these cells. Specific messenger RNA (mRNA) for differentiation markers (thyroglobulin, Tg; TSH-receptor, TSH-R; thyroperoxidase, TPO; placental angiogenic growth factor, PIGF, thyroid transcription factor 1, and PAX-8) and markers for neoplastic progression (vascular endothelial growth factor, VEGF; high-mobility group proteins, HMGI) have been analyzed. We also discuss whether the FB-1 cell line expresses certain citokines, such as interleukin (IL)-1, IL-4, IL-6, IL-8, and its responsiveness to exogenous supplementation of IL-4, IL-6, IL-8, TSH, and FCS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A thyroid cancer was surgically resected from a 68-yr-old woman at S. Chiara Hospital, University of Pisa, Italy. The tissue was cut up under sterile conditions and immersed in culture medium, frozen in liquid nitrogen, or fixed in formalin for histopathological diagnosis.
Cell culture
Neoplastic tissues were finely minced into 1-mm to 3-mm pieces with a scalpel or scissors. Fragments were washed three to five times in M-199 media supplemented with penicillin (500 U/mL), streptomycin (500 U/mL), and nystatin (1000 U/mL). Tumor tissue was suspended in DMEM medium with 10% of FCS and incubated at 37 C in 5% CO2. Primary culture reached confluence in 4 weeks. Thereafter, the cells were detached with a tripsin solution and transferred in primary tissue cultures (Becton Dickinson Labware, Bedford, MA). At passage 3, cells were plated in methocel (3) to evaluate the colony-forming efficiencies. The biggest colony was picked up and expanded in tissue-culture flasks.
Chromosome
Cell cultures, at passage numbers 12 and 34, were processed for cytogenetic analysis using standard methods (Colcemid exposure, 0.4 mg/mL for 3 h; hypotonic solution, KCl 0.56% for 30 m; methanol-glacial acetic acid, 3:1 for 30 m) (4). The QFQ banding technique was applied. Fifty methaphases were analyzed in detail, and chromosomes were classified according to the International nomenclature (ISCN, 1985). Chromosomal changes were identified as clonal, if present in at least three methaphases.
Immunocytochemistry
Immunohistochemical analysis were performed in tumor tissues obtained both from patients and from severe combined immunodeficient (SCID) mice, and in FB-1 culture cells. Tissue fragments were fixed in formalin and embedded in paraffin, whereas cells were grown in chamber slides (Nunc, Naperville, IL) and fixed in 1:1 (vol/vol) acetone-methanol at -20 C. The following antibodies were used: Tg (Dako, Milano, Italy), p53, protein bcl-2, CD34, FGF, and VEGF (Oncogene Science, Manhasset, NY). Cultures were stained with 0.5–1 µg antibody in 10 mL of PBS-BSA. Reactivity was revealed by immunoperoxidase, staining with an avidin-biotin complex kit (ABC kit; Vector, Burlinghame, CA), as already reported (5).
RNA extraction, Northern blot, and RT-PCR
RNA was isolated from cultured cells at a passage 21, by modification of the guanidine thiocyanate method (6).
Northern blot analysis. Northern blots were performed according to a standard procedure (7). Briefly, 10 µg total RNA for each cell line were size fractioned on a 1.2% denaturating formaldehyde agarose gel, blotted onto Nylon filters (Hybond-N; Amersham, International plc, UK), and probed with TG, TSH-R, TPO, PAX-8, TTF-1, VEGF, HMGI-C, and HMGI (Y)-specific complementary DNA (cDNA) probes, as already reported (8, 9, 10). Labeling of the probes was performed with the random oligonucleotide primer kit (Amersham Corp.). The 28S and 18S ribosomal RNAs were used as molecular-weight markers. Beta-actin was used as control for uniform RNA loading.
Analysis of cytokine transcripts. After treatment with ribonuclease-free deoxyribonuclease for 1 h at 37 C, cDNA was obtained by using M-MLV RT in conjunction with random hexamer primers (Clontech, Palo Alto, CA.). cDNA was then amplified by the PCR using Taq polymerase and cytokine-specific primer pairs (Cytokine MAPPing Amplimers, Clontech). Amplification was carried out for the following human transcripts: IL-4 (amplified product 344 bp), IL-6 (amplified product 628 bp), IL-8 (amplified product 289 bp), and G3PDH (amplified product 983 bp). G3PDH (human glyceraldehyde 3-phosphate dehydrogenase) was used as control of mRNA detectability. Thirty amplification cycles were performed in a Hybaid thermal reactor (Hybaid, Teddington, UK). Amplification products were separated by electrophoresis on 2.5% agarose gels and visualized under ultraviolet light by staining with 0.5 mg/mL ethidium bromide. FX174/HaeIII digest was used as size marker.
Measurement of cytokine levels
Conditioned media from FB-1 cells were used to measure the release of IL-4, IL-6, and IL-8 with immunoenzyme assays [dosage kits were from: Genzyme, Boston, MA (IL-1-a, sensitivity 5 pg/mL; IL-1-b, sensitivity 1 pg/mL) and R&D Systems, Minneapolis, MN (IL-6, sensitivity 5pg/mL; IL-8, sensitivity 30 pg/mL). FB-1-conditioned media were taken at 3, 12, and 24 days post plating (reported data refer to day 12). TPC-1 and ARO cells were used as control.
Cell response to growth regulators
Cells (5 x 103) were seeded in 48-well plates (Costar, Milano, Italy) in medium containing 10% FCS. After 24 h, cultures were washed twice and incubated with DMEM medium containing only 0.1% BSA. The influence of different citokine/growth factors on growth potential was studied: recombinant human (rh)-IL-4 (1 ng/mL; UBI, Lake Placid, NY); rh-IL-6 (1 ng/mL, UBI), rh-IL-8 (1 ng/mL, UBI), bovine TSH (Sigma Chimica, Milano, Italy), and FCS (10%; Gibco, Grand Island, NY). The cells were trypsinized and counted every 2 days for 8 days. DNA synthesis was measured as [3H] thymidine incorporation (Amersham, Milan, Italy) by cells grown in serum-free medium (SFM). FB-1, TPC-1, and ARO cells were seeded in 48-well culture plates at 5 x 103 cells/well. After 24 h, subconfluent cells were rinsed three times with SFM. Twelve hours later, 10 mL SFM containing 10 mCi/mL of [3H] thymidine were added for an additional 12 h. The cells were then rinsed three times in PBS, fixed in methanol 90, and dried. One milliliter of 0.1 N NaOH was added per well. One hour later, lysates were collected and added to 7 mL of high flash-point LSC-cocktail (Packard Instruments, Groningen, NL). Results are expressed as net cpm/50.000 cells or as percentage of untreated control cultures.
Assay of the transformed phenotype
For colony-formation in soft agar and methylcellulose, 2 x
104 cells were suspended in 0.5 mL DMEM, supplemented with
either 0.3% Agar Noble (Difco, Detroit, MI) or 0.8%
carboxymethylcellulose (Sigma), and layered on a 0.8% Agar Noble base
(0.25 mL in 2-cm2 wells). Twenty-one days post plating,
colonies 
60 µm in diameter were photographed and counted.
For tumorigenicity test, 10-million cells suspended in 0.2 mL Matrigel were injected sc into the left and right flanks of immunodeficient female SCID mice (IFFA-Credo, Milano, Italy). The animals were maintained in laminar flow cabinets and given sterile food and acidic water ad libitum. The sites of injection were inspected weekly.
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Results |
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The patient was a 68-yr-old female with an undifferentiated
thyroid carcinoma, who died of the disease 8 months after surgery.
Histologically, the tumors showed also some areas with trabecular
pattern. Immunohistochemical analysis of the primary tumor showed
absence of Tg and calcitonin immunoreactivity and less than 5%
positivity for pancytokeratin. In addition, a majority of
neoplastic cells overexpressed p53 protein, whereas only a few cells
overexpressed BCL-2. Primary tumors showed high microvessel density, as
well as immunoreactivity to angiogenic related factors such as VEGF and
FGF (Table 1
).
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).
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Modal chromosomal numbers in vitro ranged between 49
and 52. The number of cells with different number of chromosome was:
5 = 48, 7 = 49, 3 = 50, 4 = 51, 33 = 52.
The in vitro stem line was defined as: 52,XX,
+del(1)(p33), +5, +add(7)(p15), -17, der(17) (t17;22)(q21;q11), +20,
+der(22)t(17;22)(q21;q11), +mar (Fig. 2).
Random chromosome losses accounted for methaphases with chromosome
number < 52.
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Expression of TG, TPO, TSH-R, PIGF, TTF-1 and PAX 8. The FB-1
cell line was then analyzed for the expression of genes specific of
thyroid differentiation, such as TG, TPO, TSH-R, TTF-1 and PAX 8 two
transcriptional factors known (11) to be involved in the regulation of
TG and TPO; and a PIGF that is thyroid specific in adult tissues (10).
The results are presented in Fig. 3. No
PGIF TG, TSHR, or TPO was observed in FB-1 (lane 2) and in another well
known thyroid cell line deriving from an anaplastic thyroid carcinoma
(ARO, lane 3). Conversely, PAX8 and TTF-1, whose expression is thyroid
specific, is kept in the FB-1 cell line at a level comparable with that
observed in normal thyroid tissue (lane 1). In ARO cells, the
expression of PAX-8 is lost. The expression of TTF-1 and PAX-8 confirms
the thyroid origin of the FB-1 carcinoma cell line.
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shows the HMGI (Y) and HMGI-C genes are
not at all expressed in the normal thyroid (lane 1), whereas they are
abundantly expressed in FB-1 (lane 2). The expression is even higher
than that found in the ARO neoplastic cells (lane 3) and other thyroid
cell lines analyzed (data not shown). VEGF expression is present in the
normal thyroid; however, its expression is much higher in the FB1
cells.
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Conditioned media from FB-1, TPC-1, and ARO cell cultures were
tested for the presence of IL-1-, IL-1-ß, IL-4, IL-6, and IL-8. No
cultures released IL-1-, IL-1-ß, and IL-4, whereas both papillary
thyroid cancer cell lines TPC-1 and FB-1 produced high levels of IL-6.
However, the amount of IL-6 secreted by TPC-1 cells was significantly
higher than those produced by FB-1 cells. IL-8 were found in all the
conditioned media tested, although the ARO cell line secreted
significantly reduced levels of this cytokine. Analysis of mRNA
transcripts confirmed the above results. Analysis of mRNA transcripts
confirmed that no IL-4 expression was present in FB-1 cells, whereas it
expressed mRNA for IL-6 and IL-8. (Fig. 5).
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Thyroid cells are dependent on TSH and serum supplementation for
optimal differentiation and anchorage-dependent growth (12). To
evaluate the effects of FB-1 cells on the response to TSH (0.1 mU/mL, 1
mU/mL, 10 mU/mL, 100 mU/mL) serum and cytokines, the growth curve and
rate of DNA synthesis were examined in culture growth with SFM. Figure 6 shows that FB-1 cells cultured in
serum-containing medium had a cell number significantly higher than
cells cultured either in SFM or in TSH-supplemented SFM. In addition,
no difference in cell number has been found in the absence or presence
of IL-4, IL-6, and IL-8. The same data have been confirmed by
evaluation of [3H] thymidine incorporation (data not
shown).
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FB-1 cells were tested for their ability to form colonies in
semisolid media. Twenty-one days after plating, large colonies were
present both in soft agar (80 ± 10; mean ± SD)
and in methylcellulosa (103 ± 11; mean ± SD).
Fb-1 cells were injected sc into SCID female mice to evaluate their
tumorigenic potential. Between 25 and 30 days after injection, all
injected mice developed rapidly-growing tumors. Tumors were classified
as anaplastic carcinomas, although 50% of them showed areas with
trabecular pattern (Fig. 7).
Immunohistochemical analysis showed that less than 5% of neoplastic
cells were Tg and cytokeratin positive. As reported in Table 1
, the
immunophenotypical pattern showed reactivity similar to FB-1 cells in
culture.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal thyroid cells express Tg and TPO and are TSH dependent for their growth and function. Moreover, it has been reported that the expression of Tg and TPO is regulated by two thyroid-specific transcription factors: TTF-1 and PAX8. TTF-1 binds DNA in a sequence-specific manner (21) and activates transcription of Tg and TPO. The same transcriptional activity has been found (22) for PAX-8, a member of the murine family of paired box-containing genes. Like the ARO anaplastic carcinoma cell line, FB-1 cells fail to express Tg, TPO, and TSH-R mRNA. By contrast, although both transcriptional features are lost in ARO cells, FB-1 cells show a level of TTF-1 and PAX-8 transcript comparable with the normal thyroid. Also PIGF, whose expression is thyroid specific, is not expressed in the FB-1 cells.
Furthermore, the FB-1-differentiated thyroid phenotype was examined by monitoring the steady-levels of the TSH-R, as well as the responsiveness from TSH and FCS supplementation. The TSH-R expression was completely lost in our cells and, as expected, FB-1 cells were totally irresponsive to different doses of bovine TSH. However, we found that supplementation of FCS significantly increases the cell number in growth curve analysis.
Because it has been previously reported that the HMGI and VEGF expression are correlated with the malignant phenotype of thyroid cells, we analyzed the mRNA and protein expression of these two markers in FB1 cells. HMGI gene encodes for the HMGI protein family (HMGI, HMG-Y, and HMGI-C), which is involved in the regulation of the chromatin structure and function. The high expression of the HMGI proteins has been correlated with the presence of highly malignant phenotype in both epithelial and nonepithelial rat thyroid cells (23, 24). In humans, HMGI and HMGY proteins are specifically expressed in malignant thyroid tumors but are undetectable in benign neoplasia, in goiters, and in normal thyroid cells (9). The VEGF is a potent mitogen for endothelial cells in vitro, promotes neoangiogenesis in vivo, and increases the permeability of the vascular endothelium. Using thyroid carcinoma cell lines, the tumorigenic potential of the cells was associated with an elevated VEGF expression. In humans, highly malignant anaplastic thyroid carcinomas showed a 3- to 20-fold increase of the VEGF expression, compared with tissue, whereas an intermediate level of VEGF mRNA was observed in about 50% of well-differentiated carcinomas (10). We found that FB-1 cells expressed very high levels of HMGI mRNA, whereas normal cells failed to show the HMGI expression. The expression was even higher than the ARO cell line. VEGF mRNA was present in the normal thyroid; however, the expression was significantly increased in the FB-1 cell line. High VEGF expression, together with FGF (another growth factor related to tumor angiogenesis), also has been confirmed by immunohistochemical analysis.
Taken together, these data suggest that the FB-1 cells: 1) derive from thyroid cells, and 2) express differentiation markers such as TTF-1 and PAX-8; 3) are responsive to serum; but 4) express a high level of markers of aggressiveness, such as HMGI and VEGF, and e) show high tumorigenic potential.
The role of cytokines in cancer is not completely understood, although it has been a subject of intense investigation. A number of cytokine/growth factors seem to act on thyreocytes as regulators of cell growth differentiation and hormone production. Proliferation of the human thyroid carcinoma cell line, NIMI, is stimulated by the supplementation of exogenous IL-1 (25), whereas the same cytokine inhibits the DNA incorporation in the thyroid carcinoma cell line NPA (26, 27), BHP, and TPC-1 cell line (28). WRO cells, a follicular thyroid carcinoma cell line, are instead irresponsive to the exogenous IL-1 (26).
It has been reported that IL-8 is costitutively produced by TFC (29, 30). We have found recently that high IL-8 was released both by normal and neoplastic primary cultures. Although the IL-8 may play a role in the potentiation and maintenance of the autoimmune thyroid disease, the importance of these cytokines in thyroid tumor is unclear. Interestingly, we found that the TPC-1 papillary cell line and FB-1 cells produce high IL-8 levels, whereas the production of IL-8 was significantly reduced in the ARO cell line.
Like IL-8, IL-6 is costitutively produced by TFC and seems to influence the physiology of normal thyreocytes. In fact, both human and rat cell cultures, IL-6 inhibits TSH-induced thyroid peroxidase gene expression and T3 secretion. However, our recent finding that the absence of the IL-6-R expression, both in normal and neoplastic cells, rules out the possibility of IL-6 acting in an autocrine way on thyreocytes. However, as regards IL-8, no data has been reported in literature on the role of IL-6 in thyroid cancer. Well-differentiated TPC-1 cells produced high levels of IL-6, whereas the highly undifferentiated ARO thyroid cell line failed to release detectable amounts of IL-6, and FB-1 produced an intermediate level of IL-6. Taken together, these data suggest that: 1) IL-6 and IL-8 are produced in large amounts by both normal and well-differentiated carcinoma cell lines; 2) IL-6 secretion is abolished and IL-8 drastically reduced in the late stage of thyroid tumorigenesis; and 3) the FB-1 cell line is still able to secrete high IL-8 levels and medium amounts of IL-6. Because FB-1 cells still showed some differentiation markers, our data suggest that the expression and secretion of these cytokines are somehow related to the differentiation process. Hence, FB-1 cells are in between well-differentiated the TPC-1 cell line and highly anaplastic ARO carcinoma cells. In conclusion, the present results suggest [as for mammary carcinoma (31)] that IL-6 may also play a differentiative role in thyroid epithelial cells.
In our in vitro study, IL-6 failed to inhibit cell proliferation and DNA synthesis in FB-1 cells. IL-6 irresponsiveness could be caused by: 1) IL-6 production, which may influence thyroid cells sensitivity; and/or 2) the lack of IL-6 receptors (as previously found in normal and neoplastic thyreocytes) could be the cause of irresponsiveness to IL-6. However, further investigations are in progress to better understand this point. In addition, neither IL-4 nor IL-8 seems to affect the growth potential of FB-1 cells.
In conclusion, the FB-1 cell line could be an important in vitro model to investigate the biology and new therapeutic approach against this extremely aggressive neoplasia. Tests in vitro and analysis in vivo, using immunodeficient SCID mice, are in progress to evaluate whether the suppression of the IL-6 and IL-8 expression using the antisense oligonucleotyde could affect neoplastic progression.
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Footnotes |
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Received May 29, 1997.
Revised August 5, 1997.
Accepted September 9, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and interleukin-1ß on human papillary
thyroid carcinoma cell lines. J Clin Endocrinol Metab. 80:1664–1669.This article has been cited by other articles:
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