Role Of Lif In Cancer

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Several tumour cell lines and neoplastic cells from various tissues produce LIF and express LIF receptors. However, the functional significance of either LIF or LIFR in human neoplasia is not fully understood. LIF can stimulate growth, induce differentiation, or trigger apoptotic cell death of various tumour cells (1,141,150,151) and data on the mechanisms controlling this diverse array of effects are scanty.

Results of in vivo animal trials shed light on some of the possible roles of LIF in cancer and cancer metastasis. Cachexia (43,44), subcutaneous and abdominal fat loss, and elevated leukocyte and platelet counts often found in patients with metastatic cancer were induced by LIF in both mice and monkeys (46-48). In addition, at a high dose, LIF induced myelosclerosis whereas a low dose induced megakaryocytosis, reduced marrow cellularity and caused lymphopenia (48) suggesting a possible role for LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and in marrow sclerosis. Furthermore, mice engrafted with FDS-P1 cells that produce high levels of LIF developed a fatal syndrome with cachexia, atrophy of liver and kidney, and excess bone formation with increased osteoblastic activity that resulted in metastatic-type calcifications (47) implying a role for LIF in bone tumours and neoplasms metastasizing to bone.

Table 3. Effect of UF on Various Tumours

Tumour

Effect

Leukemia and MDS

LIF induces differentiation of the mouse leukemia cell line Ml(13-15).

LiF stimulates the murine leukemia cell line DA-1 (19,66,152).

LIF is produced by the human monocytic leukemia cell line THP-1 (153).

LIF is expressed in leukemia cells (140,154) and in long-term bone marrow cultures from patients with AML and MDS (155).

LIF stimulates normal marrow progenitor proliferation (139,140) but inhibits leukemia cell growth (156,157).

Lymphoma

Lymphoma cell lines producc LIF (158), and LIF production is upregulated by

Human T-cell leukemia virus-infected cells produce LIF (159). and LIF probably serves in these cells (160).

Multiple myeloma

Human myeloma cell lines (161) and plasmacytoma cells express LIF (162) and LIF receptors (163).

LIF may act as an autocrine growth factor in multiple myeloma (163,164).

Bone Tumours

LIF is constitutively expressed in bone tumour cell lines (165) and is produced by bone tumour cells (166).

LIF and L1FR were found in giant tumour cells (167,168).

LIF-stimulated growth of giant tumour cells and they exhibit osteoclastic activity (167,168).

LIF was detected in the urine of patients with bone tumours (166).

Breast Cancer

LIF stimulates the proliferation of the estrogen-dependent MCF-7 and T47-D and the estrogen-independent SK-BR-3 and BT20 cell lines (169-171). In one study (172), LIF inhibited MCF-7 cell growth.

MCF-7 cells bind LIF and like breast cancer ceils express the gpl30 receptor subunit(169,173).

MDA-MB-231 cells produce LIF but do not proliferate in response to this cytokine (170).

LIF was detected in the supernatant of the SV40-trans formed mammary epithelial cell line HBL 100 (58) but had no effect on normal mammary epithelial cell growth (169,171).

Tumours from breast cancer patients express LIF transcripts (174) and LIF mRNA (172).

LIF and LIF receptors were detected ¡n the vast majority of breast cancer tumour tissue (173).

LIF stimulates fresh breast cancer cell proliferation (169).

Kidney Cancer

The kidney cancer cell lines A-498 and ACHN produce LIF (170). Anti-LIF antibodies inhibit A-498 and ACHN cell proliferation (170), suggesting an autocrine role for LIF in these cells.

Table 3 continued on next page..

Table 3. continuing

Tumour

Effect

Prostate Cancer

The hormone-independent prostate cancer cell lines TSH, PC-3 and DV145 produce LIF and express gpl30 (170,175). Anti-LIF antibodies suppress DV145 cell growth (170).

Melanoma

The melanoma cell line SEK1 produces LIF (34,176). LIF mRNA is expressed in several melanoma cell lines (177). LIF was detected in > 60% of human melanoma specimens (178). LIF increased the expression of the intracellular adhesion molecule-1 (178).

Hepatoma

The hepatoma cell lines HuH-1 and Hep-G2 express LIF (179). LIF stimulated the expression of acute-phase proteins in the H-35 rat hepatoma line (180).

Activation of LIFR initiates the JAK signaling pathway (181).

Gastrointestinal Cancer

LIF, LIFR, and gpl30 mRNA were detected in esophageal, gastric, colon, gall bladder, and pancreatic cancer cell lines (58,179). LIF induced ap op to sis, growth inhibition, or growth stimulation of different cell lines (179).

LIF stimulated the growth of human colon cancer cell lines (182).

Central Nervous System Tumours

LIF either inhibited (183) or had no effect (184) on glioma cell lines.

LIF, LIFR, and gpl30 were detected in neuroblastoma tumour cells (185).

LIF antisense inhibited medulloblastomacell proliferation (186).

Lung Cancer

LIF is produced by the lung adenocarcinoma cell line NCI-H23 (58), and it stimulated the growth of the lung giant cell carcinoma cell line PG (187).

Oral Cavity Cancer

The oral cavity carcinoma cell line OCC-iC produces LIF (188).

Uterine Cancer

Progestine-stimulated SKUT-IB cells express LIF (189),

Choriocarcinoma

The choriocarcinoma line NJG expresses LIF and LIFR (190).

Germ Cell Tumour

Human germ cell tumour cell lines express LIF and LIFR (191).

Several in vitro studies were performed to delineate the effects of LIF on various tumours from different tissues. Though studies of cell lines often yielded conflicting results, experiments with fresh tissue confirmed LIF's role in tumour growth, disease progression, and tumour metastasis (Table 3).

4.1 Hematological Malignancies

LIF was originally characterized by virtue of its ability to induce differentiation in the murine myeloid leukemia cell line Ml, a property that it shares with IL-6 (13-15). However, LIF had no effect on the murine leukemia WEHI 3BD+ cell line that differentiates in response to IL-6 (150,192) whereas it stimulated the growth of the murine Independent DA-1 myeloid leukemia cell line (19,152). When injected into mice that had been implanted with T-22 cells, a subclone of the M1 cell line, it prolonged the animals' survival by inducing differentiation (157). LIF is also produced by the THP-1 human monocytic leukemia cell line (58).

LIF was found to be expressed in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cultured bone marrow stroma cells (155) and in human leukemia cell lines (140,154). Although LIF stimulated human normal marrow hematopoietic progenitor cell growth (139,140,193) and stroma-derived macrophage proliferation (194), it inhibited human leukemia cell growth (156,157).

LIF also affects cells of the lymphoid lineage. T-cell clone (alloreactive) from lymphocytes rejecting kidney allografts and thymic epithelial cells (55) were found to produce LIF (reviewed in 1 & 2). Whereas normal human T lymphocytes did not bind radio-iodinated LIF (164), cells infected with human T-cell leukemia virus (HTLV)-I and -II expressed LIF (159) and proliferated in response to this cytokine (160). Similarly, various lymphoma cell lines were found to produce LIF (158), and LIF production was upregulated by IL-1 (66).

Similar to IL-6, LIF plays a role in multiple myeloma (MM) cell proliferation. Human MM cell lines (161) and myeloma and plasmacytoma cells express LIF (162), LIFR, and the gp130 receptor subunit (163) and proliferate when exposed to LIF (163,164). Thus, similarly to IL-6 LIF may act as an autocrine growth factor for MM cells. The capability of LIF to induce both lytic and osteogenic effects in skeletal tissue, suggest that the osseous abnormalities typically found in MM are induced, among other factors, by LIF-producing myeloma cells.

4.2 Bone Tumours

The effects of LIF on bone remodeling with LIF inducing both osteoclastic and osteoblastic activities suggest that LIF-producing tumour cells may significantly alter bone and skeletal tissue. Because the LIF gene was found to be mapped to chromosome 22q11-q12.2 (60), a question arose whether this site might be affected by chromosomal translocations that are related to tumours of neural-crest origin such as Ewing's sarcoma and peripheral neuroepithelioma cytogenetically characterized by t(11;22)(q24;q12). It was found that the LIF gene is located far away from the Ewing's sarcoma translocation (61,195).

Nevertheless, bone tumours were found to produce high levels of LIF. Marusic et al. tested various rodent and human immortalized malignant bone tumour cell lines and found that LIF is constitutively expressed in several cell lines and is cytokine-inducible in others (165). LIF

and LIFR were found in the cytoplasm of multinucleated giant tumour cells. Furthermore, LIF-stimulated giant tumour cells displayed osteoclast immuno-cytochemical features and resorbed large amounts of dentin (167,168). Additional indirect evidence for the role of LIF in bone tumours was provided by Gouin et al. who detected LIF in 34.7% of urine samples obtained from patients with a variety of bone tumours. They also found high LIF protein levels in supernatants of both neoplastic and benign bone tumour cells (166).

Although LIF provides various bone tumours with a proliferation advantage and modulates their effects on bone tissue in either an autocrine or paracrine fashion, several studies showed that tumour cells that metastasize to bone may utilize similar mechanisms.

4.3 Breast Cancer

Because LIF affects bone tissue and is produced by marrow stroma cells (86,155), several investigators asked whether LIF has a role in tumours such as breast cancer which metastasizes to this site (196). This was further emphasized by the study of Akatsu et al. who showed that the mouse mammary cell line MMT060562 produces LIF and supports osteoclast formation via a stroma cell-dependent pathway (197).

Studies in breast cancer cell lines showed that some of these cells produce LIF, others express LIFR, and the cells may or may not respond to LIF. The diversity of cell lines and cell line clones that may have different features in different laboratories present a wide array of complex biological characteristics. For example, the estrogen-dependent breast cancer cell lines MCF-7 and T47-D do not produce LIF however their growth is stimulated by this cytokine (169-171).

MCF-7 cells bind LIF and, like several other breast cancer cell lines (172), express the gp130 subunit (169). In contrast, MDA-231 cells that express neither estrogen nor progesterone receptors produce LIF but their growth is not affected by this cytokine (170). Interestingly, progesterone treatment of MDA-231 cells co-transfected with both estrogen and progesterone induced the expression of LIF's promoter (198). LIF also stimulated the estrogen-dependent T-47D and the estrogen-independent SK-BR3 and BT20 cell lines; inhibited, according to one study, MCF-7 cells (172), but had not effect on normal mammary epithelial cell growth (169,171). Interestingly, the SV40-transformed mammary epithelium cell line HBL 100 was found to produce LIF (58).

Breast cancer cells from 6 of 6 tumour samples expressed LIF transcripts (174) and widespread LIFR mRNA expression was found in primary breast tumours (172). Immunostaining of tumour samples obtained from 50 breast cancer patients detected LIF in 78% and LIFR in 80% of the samples. The presence of LIF correlated with a low S-phase fraction of the cell cycle and diploidy, whereas the presence of LIFR correlated with dipoidy, low S-phase fraction, and of estrogen receptor positivity. LIF and LIFR were also expressed in normal breast epithelium in 87% and 77% of the specimens, respectively (173). LIF stimulated colony formation of breast cancer cells obtained from five different patients in a dose-dependent fashion (169) and the growth stimulation correlated with the presence of LIFR in these specimens (173).

Taken together the data suggest a complex role of LIF and LIFR in breast cancer growth regulation. Because the bone marrow stroma produces LIF (155) and other cytokines such as stem cell factor that stimulate breast cell proliferation (169), cells that express LIFR and respond to these cytokines may have a growth advantage in the bone marrow microenvironment.

4.4 Kidney Cancer

Renal carcinoma, like breast cancer, frequently metastasizes to bone. In addition, systemic symptoms, such as weight loss and fever, are common in kidney cancer and likely to result from overproduction of inflammatory cytokines. Moreover, the process of mouse nephrogenesis involves at least two distinct stages that can be blocked by LIF (199), and rat and human mesangial cells produce LIF and respond to this cytokine by transiently expressing the immediate-early genes c-fos, jun-B, and Egr-1 (200). These data suggest that LIF affects renal cell proliferation.

Studies with cell lines have shown that both the primary kidney cancer line A-498 and the ACHN cell line established from pleural effusion of metastatic renal carcinoma produce LIF. Anti-LIF antibodies suppressed the cells' growth and the inhibitory effect was reversed by exogenous LIF. These data suggest that the endogenously produced LIF stimulated kidney cancer cell line proliferation (170).

4.5 Prostate Cancer

Prostate cancer cells selectively metastasize to the axial skeleton to produce osteolytic lesions. Laboratory data suggest that LIF plays a role in this disease. Paracrine-mediated growth factors may play a role in prostate cancer growth and development (201). In addition, IL-6, often expressed in parallel with LIF (202), was found to be expressed in prostate tissue (175) and might stimulate prostate cancer growth during disease progression (203). The hormone-independent cancer cell lines TSU, PC-3 (204), and DU 145 (170) produce LIF and express gp130 (204). DU 145 cells did not proliferate in response to this cytokine (170,204) however, anti-LIF antibodies inhibited the cells' growth (170). Thus, although only a few studies investigated the effect of LIF on prostate cancer cells and no data on binding of LIF to cellular LIFR are available, results from the above-described studies suggest that LIF plays a role in prostate cancer.

4.6 Malignant Melanoma

In 1989, Mori et al. found that a factor produced by the melanoma cell line SEKI induced cachexia in tumour-bearing nude mice and inhibited lipoprotein lipase. This factor designated melanoma-derived lipoprotein lipase inhibitor was found to be identical to LIF (34,176). Subsequent studies found that LIF mRNA is expressed in various melanoma cell lines of which several produce the protein (58,177). Interestingly, oncostatin-M, another member of the IL-6 cytokine family, significantly increased LIF production by melanoma cells (205).

LIF was detected in more than 60% of human melanoma samples and was found to enhance the expression of the intracellular adhesion molecule (ICAM)-1 in melanoma cells (177). Shedding of the soluble form of ICAM-1 from tumour cells impairs immune recognition and leads to tumour escape. Therefore, LIF may provide melanoma cells with a survival advantage. Furthermore, melanoma cells transfected with LIFR showed increased tumour growth suggesting that LIF may directly stimulate the growth of melanoma cells that express LIFR and provide them with a survival and growth advantage.

4.7 Hepatoma

Only a few groups studied the effects of LIF in hepatoma. It was found that LIF is expressed in the HuH-7 and Hep-G2 hepatoma cell lines (179). LIF upregulated the expression of acute-phase proteins in the rat H-35 hepatoma cells (180) and activation of LIFR initiated signaling through the JAK pathway in Hep-G2 cells (181).

4.8 Gastrointestinal Malignancies

The mRNA of LIF, LIFR6, and gp130 was detected in six stomach cancer, two colon cancer, one esophageal cancer, one gall bladder cancer, and seven pancreatic cancer cell lines (179). LIF induced apoptosis in the AZ-521 gastric and the GBK-1 gall bladder cancer cell lines and was detected in the MIA PACA pancreatic carcinoma cells (58). LIF did not affect the growth of either stomach or cancer cell lines; however, it stimulated the proliferation of two of seven pancreatic cancer cell lines (171). LIF is produced by the colon carcinoma cell lines SW948 and HRT18 (58). It has been shown to enhance human colon carcinoma HT24 cell proliferation suggesting that LIF facilitates the transition from ulcerative colitis to colon cancer (182).

Because the results of cell line studies are inconsistent and since patient tumour tissue has not been studied yet, the biological significance of the cell line studies remains to be determined.

4.9 Central Nervous System Tumours

Considering the variety of effects induced by LIF in the central nervous system (CNS), its involvement in CNS tumour growth is not surprising. LIF, LIFR, and the gp130 receptor subunit were detected in medulloblastoma tumour cells. Twelve of 12 tumour samples expressed LIF, and more than 90% of the samples expressed LIFR and gp130. (185). In addition, LIF antisense inhibited medulloblastom cell proliferation (186). Taken together these data suggest that LIF acts as an autocrine growth factor in medulloblastoma.

LIF was also studied in other CNS tumours. It either inhibited (183) or had no effect (184) on glioma cell lines. Meningioma cells expressed LIF transcripts; however, LIF did not affect the cells' growth in vitro (206).

4.10 Other Neoplasms

Several groups have reported LIF's expression, production, and function in a variety of tumour cell lines. These studies implicate LIF's role in the proliferation of neoplastic cells from several malignancies.

Little is known about the role of LIF in tumours of the lung and the oral cavity. LIF is localized in the human airway mainly in fibroblasts, and IL-16 can upregulate the expression of LIF's mRNA and the release of LIF protein (207). LIF stimulated the growth of the metastatic human lung giant cell carcinoma PG cell line (187) and was found to be produced by the lung adenocarcinoma NCI-H23 cells (58) and the oral cavity carcinoma cell line OCC-1C (188).

Because of LIF's crucial role in the reproductive system, its effects on neoplasms originating from this system are of special interest. To our surprise, we were able to find only a limited number of studies addressing this issue. Bamberger et al. reported that LIF's transcription is upregulated upon exposure of the SKUT-1B uterine tumour cell line to a progesterone agonist (189). A soluble form of LIFR was detected in the supernatant of the choriocarcinoma cell line NJG, which also expressed LIF cDNA (190). Interestingly, human germ tumour cell lines express two forms of LIFR. Overexpression of LIFR of either form generated different levels of LIF protein activity, suggesting an autocrine role for LIF during germ cell tumourigenesis (191).

LIF is also expressed in several other human tumour cell lines. Those include the bladder carcinoma line 5637, the epidermal carcinoma cell line HLFa (58) the squamous carcinoma line COLO-16 (29), and the SV40-transformed keratinocyte cell line SVK14 (58). The significance of these findings is yet to be determined.

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