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Cancer is a complex disease requiring the involvement of several health care providers. A possible constant in the cancer care process is the general practitioner (GP). The aim of this project was to evaluate GPs' satisfaction with cooperation with other health care providers in the cancer care process of their patients and to explore which variables are associated with higher satisfaction with cooperation with other health care providers. We considered the following health care providers: outpatient oncology specialists, physicians in relatively small hospitals (≤400 beds), physicians in relatively large hospitals (>400 beds), home care services, outpatient psycho(onco)logists/psychotherapists, hospice/palliative care units and specialised palliative home care. The cross-sectional study was carried out as a postal survey all over Germany. Data were analysed descriptively and by means of logistic regression. Overall satisfaction with cooperation with other health care providers involved in cancer care was rather high. Only cooperation with outpatient psycho(onco)logists/psychotherapists was rated as not assessable/irrelevant by a majority of GPs. For all other health care providers under review, both communication and the transfer of sufficient information in good time were associated with overall satisfaction with cooperation. Little association was found between GP and practice variables and overall satisfaction with cooperation with the considered health care providers., (© 2017 John Wiley & Sons Ltd.)

Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A ( RhoA ) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

Objectives: The majority of Americans diagnosed as having cancer are older than 65 years. They are, however, less likely than younger patients to receive chemotherapy. Our study aimed to better understand the specific reasons for acceptance or refusal of chemotherapy in older adults with cancer., Methods: An anonymous cross-sectional survey was distributed during a 6-month study period in a cancer center and an outpatient geriatric medicine faculty practice to patients at least 50 years old with cancer or to their family members. Data collected included reasons for refusal or acceptance, stage/type of cancer, and demographics. The association between chemotherapy refusal or initiation and these factors was assessed using the Fisher exact test., Results: Among the 37 respondents meeting the inclusion criteria, 78.4% were patients and 21.6% were family members. The following factors were significantly associated with chemotherapy decision: perceived chemotherapy benefit ( P < 0.001), trust in the doctor's recommendation ( P = 0.013), social support ( P = 0.018), marital status ( P < 0.001), sex ( P = 0.037), race/ethnicity ( P = 0.021), and whether respondents had a family member or friend who had previously received chemotherapy ( P = 0.040). In contrast, none of the clinical variables, such as stage of cancer, previous receipt of chemotherapy, or interest in complementary/alternative medicine showed significant association with a patient's decision to accept or refuse chemotherapy treatment., Conclusions: Chemotherapy decisions made by older adults appear to be associated with demographic and social factors rather than with medical information. Recognizing the influence of these factors for older patients with cancer may help hematologists and oncologists to proactively address specific barriers and explore concerns regarding chemotherapy in older patients whose quality of life and longevity may be affected by treatment.

Purpose: The rising use of complementary and alternative medicine (CAM) means oncologists are increasingly asked by patients to discuss CAM treatment options. However, no formal training or established standards are available on the subject. The aim of this paper was to investigate real-world discussions of CAM treatments. In particular, we wanted to learn about the values, norms and defining features that characterise oncologist-patient discussions on CAM., Methods: Semi-standardised interviews with 17 oncologists were analysed using interpretation pattern analysis combined with thematic analysis., Results: Advice on CAM is seen by oncologists as an important service they provide to their patients, even though their knowledge of the subject is often limited. Many interviewees mentioned an apparent lack of scientific proof, especially when their aim was to warn patients against the use of CAM. Discussions on CAM tend to reflect the idea that CAM belongs 'to another world', and judging by the interviews with oncologists, this notion appears to be shared by patients and oncologists alike., Conclusions: Oncologists require reliable information on CAM and would profit from training in the communication of CAM treatment options to patients. Knowing scientific data on CAM would also lower barriers stemming from the view that CAM belongs 'to another world'. Under- and postgraduate education programmes should include training on how to respond to requests addressing possible CAM options.

Objectives: The purpose of this study was to assess and compare the perceptions of hematologists, medical oncologists, cancer patients aged 65 years and older, and family members/caregivers regarding the value of a geriatric assessment (GA) in the management of older adults with cancer., Methods: Participants included adults with cancer aged 65 years and older (n = 66), patient family members/caregivers (n = 32), and physicians (n = 42). A patient survey, a caregiver/family survey, and an online physician survey targeted to hematologists and medical oncologists were distributed at a large cancer center in a major academic health system in the New York metropolitan area. The χ(2) test or the Fisher exact test was used to compare the cohorts for responses to geriatric domains in a GA., Results: Comparisons for each of the 17 GA domains between patient and family member and caregiver responses showed concordance, except for the perception of comorbidities; 16.7% of patients indicated that comorbidities were an issue, compared with 29.0% of family/caregivers (P = 0.047). Physicians indicated that a GA would be most helpful in addressing cognitive impairment (91.4%), falls (91.4%), and functional status (88.6%)., Conclusions: A GA would be useful for physicians and older adults with cancer. Hematologists and medical oncologists recognize the utility of a GA and are receptive to a multidisciplinary geriatrics-oncology collaboration.

This is a brief history of our collaborative work with Werner and Gertrude Henle, Francis Wiener, George and Yanke Manolov, and others on the association of Epstein-Barr virus (EBV) with Burkitt lymphoma and other human tumors. Special emphasis is put on the question where EBV is a true cancer virus.

Decorin is a small leucine-rich proteoglycan, synthesized and deposited by fibroblasts in the stroma where it binds to collagen I. It sequesters several growth factors and antagonizes numerous members of the receptor tyrosine kinase family. In experimental murine systems, it acted as a potent tumor suppressor. Examining the Human Protein Atlas online database of immunostained tissue samples we have surveyed decorin expression in silico in several different tumor types, comparing them with corresponding normal tissues. We found that decorin is abundantly secreted and deposited in normal connective tissue but its expression is consistently decreased in the tumor microenvironment. We developed a software to quantitate the difference in expression. The presence of two closely related proteoglycans in the newly formed tumor stroma indicated that the decreased decorin expression was not caused by the delay in proteoglycan deposition in the newly formed connective tissue surrounding the tumor., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Humans are relatively cancer resistant, as judged by the absence of cancer in two thirds of the population. The susceptibility/resistance of other mammalians varies but shows no relationship to body size. Selection for longevity and cancer resistance may occur in parallel, as indicated by the extremely long lived and cancer free mole rat species. Microenvironmental control may play a major role in the defense against potential neoplastic cells. Our work confirms that normal fibroblasts inhibit the growth of tumor cells in vitro, largely by a contact dependent mechanism. The inhibitory capacity of the fibroblast differs depending on the site of origin, and is also different between normal and cancer derived stroma cells. Preliminary gene analysis points to major differences in gene expression in between inhibitory and non-inhibitory fibroblasts., (Copyright © 2014. Published by Elsevier Ltd.)

Increasing evidence indicates the importance of the tumor microenvironment, in particular cancer-associated fibroblasts, in cancer development and progression. In our study, we developed a novel, visually based method to identify new immunohistochemical signatures of these fibroblasts. The method employed a protein list based on 759 protein products of genes identified by RNA profiling from our previous study, comparing fibroblasts with differential growth-modulating effect on human cancers cells, and their first neighbors in the human protein interactome. These 2,654 proteins were analyzed in the Human Protein Atlas online database by comparing their immunohistochemical expression patterns in normal versus tumor-associated fibroblasts. Twelve new proteins differentially expressed in cancer-associated fibroblasts were identified (DLG1, BHLHE40, ROCK2, RAB31, AZI2, PKM2, ARHGAP31, ARHGAP26, ITCH, EGLN1, RNF19A and PLOD2), four of them can be connected to the Rho kinase signaling pathway. They were further analyzed in several additional tumor stromata and revealed that the majority showed congruence among the different tumors. Many of them were also positive in normal myofibroblast-like cells. The new signatures can be useful in immunohistochemical analysis of different tumor stromata and may also give us an insight into the pathways activated in them in their true in vivo context. The method itself could be used for other similar analysis to identify proteins expressed in other cell types in tumors and their surrounding microenvironment., (Copyright © 2013 UICC.)

Normal human and murine fibroblasts can inhibit proliferation of tumor cells when co-cultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. It requires direct cell-to-cell contact and is not transferable with supernatant. Here, we show that effective inhibition also requires the formation of a morphologically intact fibroblast monolayer before the seeding of the tumor cells. Interference with the formation of the monolayer impairs the inhibition. Subclones of TERT-immortalized fibroblasts were selected on the basis of differences in the growth pattern and related inhibitory activity. Whereas the well-organized "whirly" (WH) growth pattern was associated with strong inhibition, the disorganized "crossy" (CR) growth pattern was linked to reduced inhibition. Time lapse imaging of tumor-fibroblast co-cultures using extended field live cell microscopy revealed that fibroblast monolayers with growth inhibitory capacity also reduced the motility of the tumor cells whereas noninhibitory monolayers had no effect on tumor cell motility. Gene expression pattern of two isogenic pairs of fibroblasts, WH and CR subclones of the TERT immortalized line (inhibitory, and less inhibitory subsequently) and freshly explanted skin (inhibitory) and hernia (noninhibitory) fibroblasts derived from the same patient, identified a set of genes that co-segregated with the inhibitory phenotype. This suggests that our model system may reveal molecular mechanisms involved in contact-mediated microenvironmental surveillance that may protect the organism from the outgrowth of disseminated tumor cells., (Copyright © 2012 UICC.)

Aims: This paper describes our process to engage regional stakeholders for prioritizing comparative effectiveness research (CER) in cancer diagnostics. We also describe a novel methodology for incorporating stakeholder data and input to inform the objectives of selected CER studies., Materials & Methods: As an integrated component to establishing the infrastructure for community-based CER on diagnostic technologies, we have assembled a regional stakeholder group composed of local payers, clinicians and state healthcare representatives to not only identify and prioritize CER topics most important to the western Washington State region, but also to inform the study design of selected research areas. A landscape analysis process combining literature searches, expert consultations and stakeholder discussions was used to identify possible CER topics in cancer diagnostics. Stakeholders prioritized the top topics using a modified Delphi/group-nominal method and a standardized evaluation criteria framework to determine a final selected CER study area. Implementation of the selected study was immediate due to a unique American Recovery and Reinvestment Act funding structure involving the same researchers and stakeholders in both the prioritization and execution phases of the project. Stakeholder engagement was enhanced after study selection via a rapid analysis of a subset of payers' internal claims, coordinated by the research team, to obtain summary data of imaging patterns of use. Results of this preliminary analysis, which we termed an 'internal analysis,' were used to determine with the stakeholders the most important and feasible study objectives., Results: Stakeholders identified PET and MRI in cancers including breast, lung, lymphoma and colorectal as top priorities. In an internal analysis of breast cancer imaging, summary data from three payers demonstrated utilization rates of advanced imaging increased between 2002 and 2009 in the study population, with a great deal of variability in use between different health plans. Assessing whether breast MRI affects treatment decisions was the top breast cancer study objective selected by the stakeholders. There were other high-priority research areas including whether MRI use improved survival that were not deemed feasible with the length of follow-up time following MRI adoption., Conclusion: Continuous stakeholder engagement greatly enhanced their enthusiasm for the project. We believe CER implementation will be more successful when undertaken by regional stakeholders.

Increasing evidence indicates that cancer development requires changes both in the precancerous cells and in their microenvironment. To study one aspect of the microenvironmental control, we departed from Michael Stoker's observation (Stroker et al, J Cell Sci 1966;1:297-310) that normal fibroblasts can inhibit the growth of admixed cancer cells (neighbour suppression). We have developed a high-throughput microscopy and image analysis system permitting the examination of live mixed cell cultures growing on 384-well plates, at the single cell level and over time. We have tested the effect of 107 samples of low passage number (<5) primary human fibroblasts from pediatric and adult donors, on the growth of six human tumor cell lines. Three of the lines were derived from prostate carcinomas, two from lung carcinomas and one was an EBV transformed lymphoblastoid line. Labeled tumor cells were grown in the presence of unlabeled fibroblasts. The majority of the tested fibroblasts inhibited the proliferation of the tumor cells, compared to the control cultures where labeled tumor cells were co-cultured with unlabeled tumor cells. The proliferation inhibiting effect of the fibroblasts differed depending on their site of origin and the age of the donor. Inhibition required direct cell contact. Mouse 3T3 fibroblasts inhibited the growth of SV40-transformed 3T3 cells and human tumor cells, showing that the inhibitory effect could prevail across the species barrier. Our high-throughput system allows the quantitative analysis of the inhibitory effect of fibroblasts on the population level and the exploration of differences depending on the source of the normal cells.

Background: Many different genetic alterations are observed in cancer cells. Individual cancer genes display point mutations such as base changes, insertions and deletions that initiate and promote cancer growth and spread. Somatic hypermutation is a powerful mechanism for generation of different mutations. It was shown previously that somatic hypermutability of proto-oncogenes can induce development of lymphomas., Methodology/principal Findings: We found an exceptionally high incidence of single-base mutations in the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) both located in 3p21.3 regions, LUCA and AP20 respectively. These regions contain clusters of tumor suppressor genes involved in multiple cancer types such as lung, kidney, breast, cervical, head and neck, nasopharyngeal, prostate and other carcinomas. Altogether in 144 sequenced RASSF1A clones (exons 1-2), 129 mutations were detected (mutation frequency, MF = 0.23 per 100 bp) and in 98 clones of exons 3-5 we found 146 mutations (MF = 0.29). In 85 sequenced RBSP3 clones, 89 mutations were found (MF = 0.10). The mutations were not cytidine-specific, as would be expected from alterations generated by AID/APOBEC family enzymes, and appeared de novo during cell proliferation. They diminished the ability of corresponding transgenes to suppress cell and tumor growth implying a loss of function. These high levels of somatic mutations were found both in cancer biopsies and cancer cell lines., Conclusions/significance: This is the first report of high frequencies of somatic mutations in RASSF1 and RBSP3 in different cancers suggesting it may underlay the mutator phenotype of cancer. Somatic hypermutations in tumor suppressor genes involved in major human malignancies offer a novel insight in cancer development, progression and spread.

Two of three humans never get cancer. Even the majority of heavy smokers remain cancer free. Is this a matter of chance, or are there cancer-resistant genotypes? Based on the evidence discussed, it would appear that evolution has favored a limited number of relatively common resistance genes that may nip incipient cancerous foci in the bud, i.e., to stop them at their inception. It is further suggested that resistance genes may act at the level of tissue organization in a dominant fashion.

Traditionally, surveillance against cancer was thought of as mainly immunological. With the exception of tumors with a clear viral involvement, such as immunoblastomas (Epstein-Barr virus, EBV), cervical, anogenital, and skin carcinomas (HPV), and Kaposi's sarcoma (HHV-8) where the immune system is confronted with virally encoded, nonself targets, tumors with no viral involvement provide poor targets. Attempts to influence them by immunological means are akin to the breaking of tolerance. Robust nonimmunological surveillance mechanisms include DNA repair-based checkpoint functions, and the triggering of growth arrest and/or apoptosis pathways by DNA damage or by illegitimate oncogene activation (intracellular surveillance). There is emerging evidence for epigenetic surveillance, reflected in the stringency of imprinting. A fourth mechanism, intercellular surveillance, or microenvironmental control, is rapidly gaining momentum. It can be mediated by contactual controls or by differentiation-inducing signals. Somatic hybridization experiments have shown that tumorigenicity is usually suppressed in somatic hybrids between normal and malignant cells, as long as a fairly complete chromosome complement is maintained. Individual normal cell-derived chromosomes may have a similar suppressive effect. For example, genetic and molecular dissection of human 3p that shows frequent deletions in many human tumors has identified multiple tumor suppressor genes, which can inhibit both in vitro growth and in vivo tumorigenicity. In addition, five genes were found with an "asymmetric activity," capable of suppressing tumorigenicity, without affecting in vitro growth. These genes, LTF, L1MD1, HYAL1, HYAL2, and VHL, are of particular interest because they may be involved in microenvironmental control.

Background: Few studies have investigated cancer risks in carbon black workers and the findings were inconclusive., Methods: The current study explores the mortality of a cohort of 1535 male German blue-collar workers employed at a carbon black manufacturing plant for at least one year between 1960 and 1998. Vital status and causes of death were assessed for the period 1976-98. Occupational histories and information on smoking were abstracted from company records. Standardised mortality ratios (SMR) and Poisson regression models were calculated., Results: The SMRs for all cause mortality (observed deaths (obs) 332, SMR 120, 95% CI 108 to 134), and mortality from lung cancer (obs 50, SMR 218, 95% CI 161 to 287) were increased using national rates as reference. Comparisons to regional rates from the federal state gave SMRs of 120 (95% CI 107 to 133) and 183 (95% CI 136 to 241), respectively. However, there was no apparent dose response relationship between lung cancer mortality and several indicators of occupational exposure, including years of employment and carbon black exposure., Conclusions: The mortality from lung cancer among German carbon black workers was increased. The high lung cancer SMR can not fully be explained by selection, smoking, or other occupational risk factors, but the results also provide little evidence for an effect of carbon black exposure.

Rapid identification of human carcinogens before their dissemination into society, and exposure of worker and lay populations is an important goal of cancer research. Retroactively, verification of in-place human carcinogens is also required to target their removal, and other preventive and therapeutic strategies. The hierarchy of methods used historically for evaluation of carcinogenic potential is epidemiology > animal bioassays > mechanistic studies, and the focus has been on single agents that are genotoxic. However, mechanistic research has revealed several obligatory steps in carcinogenesis, tumor promotion, and progression that can now be used in screening studies with human cells in vitro and animal bioassays. These approaches should be combined with molecular epidemiology and molecular pathology to identify human carcinogens with more emphasis on evaluating combinations of suspect agents and mechanisms of action of epigenetic carcinogens.

Initial analysis identified the NPRL2/G21 gene located in 3p21.3C, the lung cancer region, as a strong candidate tumor suppressor gene. Here we provide additional evidence of the tumor suppressor function of NPRL2/G21. The gene has highly conserved homologs/orthologs ranging from yeast to humans. The yeast ortholog, NPR2, shows three highly conserved regions with 32 to 36% identity over the whole length. By sequence analysis, the main product of NPRL2/G21 encodes a soluble protein that has a bipartite nuclear localization signal, a protein-binding domain, similarity to the MutS core domain, and a newly identified nitrogen permease regulator 2 domain with unknown function. The gene is highly expressed in many tissues. We report inactivating mutations in a variety of tumors and cancer cell lines, growth suppression of tumor cells with tet-controlled NPRL2/G21 transgenes on plastic Petri dishes, and suppression of tumor formation in SCID mice. Screening of 7 renal, 5 lung, and 7 cervical carcinoma cell lines showed homozygous deletions in the 3' end of NPRL2 in 2 renal, 3 lung, and 1 cervical (HeLa) cell line. Deletions in the 3' part of NPRL2 could result in improper splicing, leading to the loss of the 1.8 kb functional NPRL2 mRNA. We speculate that the NPRL2/G21 nuclear protein may be involved in mismatch repair, cell cycle checkpoint signaling, and activation of apoptotic pathway(s). The yeast NPR2 was shown to be a target of cisplatin, suggesting that the human NPRL2/G21 may play a similar role. At least two homozygous deletions of NPRL2/G21 were detected in 6 tumor biopsies from various locations and with microsatellite instability. This study, together with previously obtained results, indicates that NPRL2 is a multiple tumor suppressor gene.

In the past decades, a lot of effort has been put in identifying the role of matrix metalloproteinases (MMPs) in cancer. The main role of MMPs in angiogenesis, tumor growth and metastasis is degradation of extracellular matrix (ECM) and release and/or activation of growth factors through their degradative activity. The degradative activity finally results in cancer progression. MMP-inhibitors (MMPIs) have already been designed and tested, based on the degradative role of MMPs in cancer progression. First clinical trials with MMPIs have been performed with disappointing results, showing that in order to use MMP-inhibition the mechanisms underlying MMP-expression in cancer have to be further elucidated. This paper reviews the mechanisms of MMPs on molecular and cellular level and discusses the role for MMPs and MMP-inhibition in cancer with special focus on acute leukemia.

Following the ingenious prediction of Alfred Knudson in 1971, the first tumor suppressor gene, RB1, has been isolated. Its product, the RB1 protein, was found to play a major role in the control of the cell cycle. The loss of heterozygosity (LOH) technique, introduced by Cavenee and colleagues, was an important milestone toward the confirmation of Knudson's hypothesis and the identification of the gene. Subsequently, the LOH technique has provided important clues that have led to the discovery of other tumor suppressor genes. Most of them play important roles in the regulation of the cell cycle and/or of apoptosis. Circumstantial evidence suggests that still other and perhaps many unknown genes may participate in the protection of the organism against malignant growth. The numerous genome losses in tumors, detected by LOH, comparative genomic hybridization, and by cytogenetic techniques, support this possibility. The early work of one of us (G.K.), together with Henry Harris and Francis Wiener, had shown that the malignant phenotype can be suppressed by hybridizing malignant with low- or non-tumorigenic cells. However, analysis of this phenomenon failed to assign the inhibition of tumorigenicity to any particular gene. We have pursued the search for new tumor-antagonizing genes with two unconventional approaches, focusing on human chromosomal subband 3p21.3, a region frequently targeted by cytogenetically detectable deletions. We have detected four clusters of candidate tumor suppressor genes at 3p21.3 by a combination of deletion mapping and the "elimination test." These findings raise the question whether the number and variety of genes that may contribute to the defense against uncontrolled proliferation may have been underestimated., (Copyright 2003 Wiley-Liss, Inc.)

To facilitate the identification of tumor suppressor genes in the chromosome 3p21.3-p22 AP20 subregion, we constructed a 3.5-Mb physical and gene map of this segment (between markers D3S4285 and D3S3873) that spans the distance from 124.4cR3000 to 133.5 cR3000 of the GB4 genetic map. We used NotI-linking and -jumping clones, sequence-tagged site PCR marker analysis, and multicolor and fiber fluorescence in situ hybridization to confirm the sequence order and map orientation. An integrated clone contig composed of 5 yeast artificial chromosome, 15 bacterial artificial chromosome, 5 P1 artificial chromosome, and 8 NotI-linking clones provided the physical base of the map. We unequivocally established the order of 28 sequence-tagged sites and 35 genes in the region. Gaps between published bacterial artificial chromosome contigs were determined and covered by our own sequence data. Furthermore, three new genes were isolated, namely the human homologue to the rat Golgi peripheral membrane protein p65, GOLPH5 (GORASP1), the gene for stress-inducible protein, STI2, and the AP20-region gene 1, APRG1. The tumor suppressor gene candidate APRG1 was positioned close to the border of the homozygous deletion in a small cell lung cancer cell line ACC-LC5. Expression analysis with a tissue-specific panel of cDNA revealed seven distinct tissue-specific splice variants (A-G) of the message (size range, 1.0-1.8 kb). Although the gene was expressed at a low level in all tested tissues, comparatively higher expression was detected in pancreas (splice forms B and D), kidney (A) and placenta (B and C). The APRG1 gene encoded a predicted protein of 170 amino acids (isoform B), which had an NH2-terminal part conserved among members of the eukaryotic translation factor 6 gene family. A Prosite pattern corresponding to the cell attachment sequence Arg-Gly-Asp was also found. The presence of this domain raised the intriguing possibility that APRG1B may be directly involved in membrane interactions and cell adhesion. We showed that the AP20 region was duplicated during mammalian evolution and homologous gene clusters were present in human chromosome 2 and syntenic mouse regions on chromosomes 1, 2, and 9. Interestingly, the HYA22 gene (human ortholog of the yeast YA22 gene) was located at the borders of both breakpoints, evolutionarily conserved gene cluster and homozygous deletions detected in lung, kidney and other cancers. NotI digestion revealed that the AP20 region was frequently and extensively methylated in renal carcinoma cell lines and tumor biopsies.

Occurrence of chromosome 3p deletions in a large number of human tumours suggests the existence of uncharted tumour suppressor gene(s). We previously applied a functional assay, named the Elimination test (Et), for the identification of regions containing tumour growth antagonising genes. This resulted in the definition of chromosome 3 common eliminated region 1 (C3CER1) on 3p21.3, which is regularly eliminated from SCID-derived tumours. Systematic genomic sequencing of 11 PAC clones, combined with comparisons of genomic sequence against EST databases and PCR-based cloning of cDNA sequences allowed us to assemble a comprehensive transcriptional map of 1.4 Mb that includes 19 active genes and three processed pseudogenes. We report four novel genes: FYVE and coiled-coil domain containing 1 (FYCO1), transmembrane protein 7 (TMEM7), leucine-rich repeat-containing 2 (LRRC2) and leucine zipper protein 3 (LUZP3). A striking feature of C3CER1 is a presence of a cluster of eight chemokine receptor genes. Based on a new analysis of the microcell hybrid-derived panel of SCID tumours we also redefined the centromeric border of the C3CER1. It is now located within LRRC2 gene, which is a relative of RSP-1 (Ras Suppressor Protein 1). The detailed knowledge of gene content in C3CER1 is a prerequisite for functional analysis of these genes and understanding of their possible role in tumorigenesis.

Most forms of cancer arise through a Darwinian evolutionary process. The natural selection that ultimately leads to cancer takes place in somatic tissues although it may be triggered by inherited mutations in a small but significant minority. It favors the growth of clones and subclones that are less and less responsive to normal intra- and extracellular growth control mechanisms. The development of molecular biology has led to the identification of many genes that participate in this somatic evolution. They belong to the following groups: Oncogenes, constitutively activated by structural and/or regulatory changes that drive the cell to continuous proliferation; Tumor suppressor genes, that can inhibit the illegitimately activated cell cycle. They contribute to tumor development by loss mutations or permanent down-regulation, e.g. by methylation; Apoptosis inhibitory genes that can contribute to tumor development by raising the apoptotic threshold, and apoptosis promoting genes that can favor the growth of apoptosis prone tumor cells by their loss or inactivation; DNA repair genes whose inactivation can counteract the normal elimination of cells that carry potentially cancer promoting mutations. Inherited mutations in DNA repair genes can lead to familial cancer syndromes. Immortalizing genes that counteract cellular senescence; Angiogenesis promoting genes whose products may stimulate the vascular supply of tumors; Genes whose structural or functional changes may facilitate the escape of tumor cells from immune rejection; The multi-step development of individual tumors can encompass changes in most or all of these genes. They occur independently of each other and without any fixed order or timing. Tumor emancipation from growth control can therefore proceed along various pathways. It follows that each tumor must be regarded as a biologically unique individual.

By applying the 'recognition mask' strategy to 300 mammalian sequences containing NotI sites we demonstrated that 5' ends of genes are highly enriched in NotI sites. A NotI linking clone NL2-252 (D3S1678) containing transferrin receptor (TFRC) gene was used as an initial point for chromosomal jumping. One of the jumping clones, J21-045 traverses 210 kbp and links NL2-252 to NL26 (D3S1632), a NotI linking clone containing highly polymorphic sequences. The TFRC gene was mapped to 3q29, close to the telomeric marker D3S2344, by linkage analysis, a panel of hybrid cell lines, GeneBridge 4 panel and FISH. Clone NLM-007 (D3S4302) was found to contain ras-homologous gene RAB7. By FISH and a panel of hybrid cell lines this gene was mapped to 3q21. This region is of particular interest due to frequent rearrangements in different types of leukemia. Clone L2-081 (D3S4283) containing new member of ubiquitin-specific proteases (HAUSP gene) was localized in 3p21 inspiring further investigation of involvement of this gene in development of lung and renal carcinomas.

Long-range restriction site maps are of central importance for mapping the human genome. The use of clones from linking and jumping libraries for genome mapping offers a promising alternative to the laborious procedures used up until now. In the present review, this research field is analyzed with particular emphasis on the implementation of a shot-gun sequencing strategy for genome mapping and the use of NotI linking clones for analysis of rearrangements in tumors and tumor cell lines.

Self-expandable metal stents 7 mm in diameter were percutaneously implanted into 13 ureters in 10 patients with malignant ureteral obstruction not amenable to double-J stent placement. In nine ureters, one stent was placed, and in four ureters, two overlapping stents were placed. Primary reconstitution of ureteral patency was achieved in all ureters. After 1-2 weeks, four ureters showed a urothelial reaction encroaching on the lumen of the ureter, and a double-J stent was placed coaxially. One ureter was occluded by urothelial hyperplasia 4 weeks after stent placement, and a double-J stent was therefore placed. One ureter was occluded 8 months after stent placement by distal tumor overgrowth. The other ureters showed no signs of obstruction during a follow-up of 3-14 (average, 5.8) months. Peristalsis was preserved at both ends of the stent in all ureters. The use of this stent alone or in combination with a double-J stent alleviated upper urinary tract obstruction and avoided external drainage in all patients.

Human mitomycin C-treated PBL were mixed with cells of an NK sensitive hybrid cell line (PUTKO-I). A fraction of tumor cells survived this treatment and could be recovered from the cultures. These surviving cells were completely NK-resistant and this property persisted for 2-3 weeks after cultivation in fresh medium. Treatment of a clone (C13) of PUTKO-I with PBL-PUTKO mixed lymphocyte-tumor-cell culture (MLTC) supernatants resulted in a marked reduction in NK sensitivity after 8-12 h of treatment. The kinetics of induction of NK resistance by MLTC supernatants was similar to that of purified IFN-gamma and was faster than for IFN-alpha. The active component in the supernatants was characterized as a mixture of IFN-gamma and IFN-alpha based on neutralization of activity with specific antisera. The role of mycoplasma contamination was investigated and it was found that cell lines free of detectable mycoplasma stimulated production of NK-protective activity by PBL and this activity was neutralized by anti-IFN-gamma serum. Separation of PBL on discontinuous Percoll gradients demonstrated a correlation between the NK activity of cell fractions and their ability to produce IFN in response to tumor cells. Taken together, the selection-dependent variations in NK sensitivity, the kinetics of IFN production and induction of resistance suggest that tumor cells may be able to escape elimination by NK cells due to protection by IFN produced by the effector-cell-containing population.

The regular activation of the c-myc oncogene by juxtaposition to one of the immunoglobulin loci by chromosomal translocation in Burkitt's lymphoma (BL), mouse plasmacytoma and rat immunocytoma indicates that these translocations represent an essential, i.e. rate limiting step in the development of these tumors. Since the myc-carrying chromosome appears to break at random, but preserves the integrity of the two coding exons, the exclusive involvement of myc (rather than other oncogenes) requires special comment. It must be relatable to the specific functional features of the precursor cells and to the normal role of the myc protein. Recent evidence indicates that the myc gene is regularly turned off before or at the time when the cell enters a pathway that is programmed to lead it towards a resting G0 state. Clonally expanded B-cells are believed to turn into resting memory cells upon waning of the antigenic stimulus. The normal, non-translocated myc-allele is regularly switched off in both BL and murine plasmacytoma (MPC), indicating that the cell has already obeyed a program that involves the down regulation of myc. The Ig-juxtaposed, translocated myc remains highly expressed, however, and may be responsible for keeping the cells in cycle. The possibility that BL and MPC may arise from candidate memory cells, rather than pre-B cells, is also suggested by the fact that all BL-tumors and derived lines make a heavy chain. Since the myc/Ig juxtaposition is a special case of a non-functional rearrangement, this is only expected if the precursor cell would have been preselected for a functional Ig-product. The memory cell hypothesis is further supported by the fact that the majority of BLs make IgM, most MPC make IgA and the rat immunocytomas make IgE. This could correspond to the most frequent type of the memory cell in the anatomical areas and under the physiological or pathophysiological conditions associated with the natural history of each tumor. This brief review is restricted to oncogene activation by chromosomal translocations in B-cell derived tumors.

Continued monitoring of a family for new malignant tumors has revealed diverse immunological and neoplastic disorders during a 15-year period. In 1966, the proband developed lymphoma. In 1975, his antibody titers to Epstein-Barr virus (EBV) became elevated, and again, he developed a malignant lymphoma. He also had borderline hypo-immunoglobulin A, died of glioblastoma multiforme in 1977, and at autopsy, had adenomatous colonic polyps. His eldest brother has normal immunoglobulin levels, but developed immune thrombocytopenia in 1973 and had elevated EBV antibody titers in 1980. Another brother had hypo-immunoglobulin A, thymoma in 1965, and adenomas and adenocarcinoma of the colon. Two other brothers succumbed to glioblastoma in 1968 and 1969. The father of the proband had bronchiectasis in 1952, hypo-immunoglobulin M documented in 1972, and elevated EBV antibody titers 5 years preceding development of a malignant lymphoma. The latter contained 10 EBV genome equivalents/cell by EBV viral DNA/DNA reassociation kinetics analysis. The proband's grandmother had died of an immunoglobulin G-secreting myeloma in 1977, and his grandfather had borderline low immunoglobulin M, elevated EBV antibody titers, and hypopharyngeal carcinoma in 1980. Predisposition to oncogenesis in this family was probably inherited.

There is excellent evidence for the belief that immune surveillance mechanisms prevent the outgrowth of potentially neoplastic cells induced by horizontally transmitted, ubiquitous, potentially oncogenic viruses, indigenous to natural populations. Polyoma virus in mice, Marek's disease in the chicken, Herpesvirus saimiri in the squirrel monkey, and the Epstein-Barr virus in man are examples. There is much less evidence for immune surveillance against chemically induced tumors. It is argued that surveillance against the virus-induced tumors may have evolved by the selective fixation of appropriate immune responsiveness (IR) genes. It is important to distinguish between the breakdown of an existing surveillance mechanism, e.g., by immunosuppresion, and the lack of immune recognition, due to the deficiency of the IR gene equipment. Presently available in vitro lymphocytotoxicity tests are not yet developed to the point where they can reliably distinguish between these alternatives.