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At least 19 recordsLinked to original sources
PubMed1989

Tumor heterogeneity, tumor size, and radioresistance.

Mutant clonogenic cells, resistant to individual chemotherapeutic agents, are known to play a central role in clinical chemotherapy failure. The possibility that mutant cells, resistant to conventionally fractionated megavoltage photon radiotherapy, exist in human tumors is considered. Applying the mutation theory of Luria and Delbruck to describe the appearance of resistant cells, several conclusions follow: (a) the mean number of resistant cells in a tumor will be determined by the tumor size and the mutation rate; (b) a wide variation in radiosensitivity in tumors of the same histology is expected, because of a large variation in the number of resistant cells that they contain; (c) the presence of a resistant clone will not reduce the tumor-control probability until the tumor becomes sufficiently large; (d) initial response will not be a reliable predictor of long-term control; (e) clonogenic assays may not accurately predict treatment outcomes; (f) the mutation rate may be the most accurate predictor of tumor aggressiveness and resistance to various treatment modalities; (g) tumors with a low mutation rate, which may include seminoma, Hodgkin's disease and many pediatric tumors would be curable by either chemotherapy or radiation; (h) pleomorphic tumors with a high mutation rate, which may include glioblastoma multiforme, would be difficult to cure by any means. Clinical and experimental evidence is reviewed for the existence of radioresistant cell lines in human and animal tumors, and further experiments are proposed to test this hypothesis. Treatment strategies for targeting radioresistant clones are discussed.

Animals↗
PubMed1983

Isopycnic density-gradient centrifugation: a separation parameter which improves flow cytometric measurements on heterogeneous tumors.

The analytic and prognostic value of flow cytometric measurements can generally be improved by preseparation of cells. The present data demonstrate clearly the distinct character of bands obtained in density-gradient separation. Density-gradient centrifugation in Percoll after extensive Ca2+ + Mg2+ elimination helps to resolve more detail in flow cytometric measurements (e.g., additional DNA stem lines in human tumors) and can be used in studies of tumor heterogeneity. The significance of investigations of tumor heterogeneity is demonstrated by the different reactivity of subpopulations of the experimental murine tumor S 180 to vincristine.

Animals↗
PubMedDate not supplied

Visual pathway tumor: a heterogeneous tumor with a variable clinical course.

The aim of the study was to delineate the clinical characteristics of visual pathway tumor in children without neurofibromatosis-I. The authors reviewed the charts of all patients meeting these criteria (n = 12) who were followed in their center over a 13-year period. In 8 patients the disease was relentlessly progressive, and imaging showed a chiasmatic/hypothalamic, exophytic globular lesion. The remainder had a benign course with long periods of tumor stability; one showed some spontaneous visual improvement. The lesions of the latter subgroup were multilobular, with elongated posterior extension into the optic tract. This differentiation, according to the imaging findings, may have significant therapeutic implications. In the first type, every effort should be made to arrest the disease and decrease the size of the lesion, whereas in the second, despite decreased visual ability, careful observation in the appropriate approach. There are as yet no known biological markers to better delineate these two types of tumor behavior.

Cranial Nerve Neoplasms↗
PubMed2002

Prediction of tumor heterogeneity in localized prostate cancer.

Clinical T1 and T2 prostatic carcinoma is a heterogeneous tumor with respect to pathologic stage and outcome. In the authors' experience, 60% of patients have a pT2 prostatic carcinoma, and 2% to 4% have tumors less than 0.5 cm3 in volume. The latter group cannot be predicted by the use of preoperative parameters with a sufficient sensitivity and specificity. Quantitative analysis of six systematic biopsies, that is, reporting the number of biopsies with any Gleason grade 4 or 5 cancer or the number of biopsies with more than 50% Gleason grade 4 and 5 cancer, together with preoperative PSA levels can be used to predict the different pathologic stages and risk groups of patients with T1 or T2 prostatic carcinoma. CART analysis that using these preoperative parameters can predict the lymph node stage and the capsular penetration on each side of the prostate with a sufficient positive and negative predictive value and a sufficient specificity to avoid routine lymphadenectomy in approximately 80% of the patients classified as a low-risk group for having lymph nodes positive for disease. CART analysis also allows a solid identification of patients in whom the unilateral or bilateral nerve may be spared during surgery. These algorithms may be improved further by determining the HK-2 level in the blood or by including other molecular biologic markers in the analysis of the biopsies. Clinical T1 or T2 prostatic carcinoma is a heterogeneous but fairly predictable tumor.

Biopsy↗
PubMed1987

Granular cell tumors: evidence for heterogeneous tumor cell differentiation. An immunocytochemical study.

Eighteen granular cell tumors from various sites were examined with antisera directed against protein S-100, neuron specific enolase (NSE), alpha-1-antichymotrypsin, and alpha-1-antitrypsin, glial fibrillary acidic protein (GFAP), lysozyme, factor VIII-related antigen, myoglobin and vimentin, as well as with a monoclonal antibody (lu-5) directed against a panepithelial marker. The immunocytochemical reaction pattern of the tumors was heterogeneous. The brain and pituitary tumors and one thyroid tumor reacted for alpha-1-antichymotrypsin and alpha-1-antitrypsin, but not for S-100 protein and NSE. However, tumors from other sites showed immunoreactions for S-100 protein and NSE and some also for vimentin. Reactions for alpha-1-antichymotrypsin and alpha-1-antitrypsin were not observed. All other reactions were similarly negative. We conclude that the morphologically homogeneous group of granular cell tumors is biologically heterogeneous.

Cell Differentiation↗
PubMed1993

Prognostic value of karyometric and clinical characteristics in renal cell carcinoma. Quantitative assessment of tumor heterogeneity.

BACKGROUND: The variation in tumor cell differentiation within one renal cell carcinoma, also termed tumor heterogeneity, renders visual tumor grading of these carcinomas difficult. Karyometric analysis enables description of nuclear characteristics of multiple tumor areas. Hence, karyometric analysis can be used to quantify tumor heterogeneity and thus may aid in a more objective grading of renal cell carcinoma. METHODS: In 121 patients with renal cell carcinoma (tumors in International Union Against Cancer [UICC] stages I [5 cases], II [23 cases], III [33 cases], and IV [60 cases]), clinical and karyometric features were studied to obtain routinely applicable prognostic factors. Several parts of the tumor were analyzed to obtain a measure of tumor heterogeneity. Univariate and multivariate Cox regression analyses were used to determine the predictive value of karyometric features independent of tumor stage and other clinical characteristics. RESULTS: The Cox univariate regression analysis showed correlation of several clinical and karyometric characteristics with survival. Of the clinical characteristics, TNM stage, tumor size, weight reduction, and performance status were significantly associated with survival. The karyometric features, especially those measurements associated with tumor heterogeneity (e.g. differences in nuclear size or chromatin texture between tumor subpopulations) were of value in predicting prognosis. In the Cox multivariate regression analysis, the Robson and UICC stages proved to be the most powerful predictors of survival (P < 0.0001). Of the clinical features, weight reduction and performance score were the only characteristics offering additional information regarding tumor stage (P < 0.0001). From the karyometric analysis quantification of anisokaryosis in the tumor at time of diagnosis offered additional prognostic information. Moreover, the differences of karyometric features within the tumor presumably associated with tumor heterogeneity correlated with survival. Using the features from the multivariate analysis, prognostic groups could be defined. CONCLUSION: We conclude that karyometric analysis offers a useful means for quantifying tumor heterogeneity. Multivariate Cox analysis revealed additional value of a grading system based on karyometric analysis to tumor stage. Karyometric analysis can be a useful tool for stratification of patient populations.

Adult↗
PubMed1996

Malignant rhabdoid tumor in adults--heterogenous tumors with a unique morphological phenotype.

Five cases of malignant rhabdoid tumors in adult patients are described. The tumors were characterized by sheets of poorly cohesive cells with distinctive hyaline cytoplasmic inclusions and eccentrically placed large vesicular nuclei with prominent nucleoli. A variety of lineage differentiation was shown by immunohistochemistry and electron microscopy, the lesions representing leiomyosarcoma, gastric carcinoma, epithelioid sarcoma, Merkel cell carcinoma and desmoplastic small round cell tumor. Previously reported cases of rhabdoid tumors in adults support the contention that such tumors, although of distinctive morphologic phenotype, are of heterogenous lineage differentiation, and do not represent a distinct clinicopathologic entity.

Adult↗
PubMed1995

Tumor heterogeneity and immunotherapy of cancer.

Tumor heterogeneity is the presence of intercellular differences, either from clonal origin or present within subpopulations of tumor cells. Recent advances in immuno-histology, flow cytometric analysis, molecular biological techniques, and tissue culture methods makes it possible to investigate tumor heterogeneity in detail. In this review data are presented to document that this hallmark of neoplastic disease results from DNA-instability and the interactions of tumor cells with their environment. The present inability to treat most patients effectively with immunotherapy may partly be due to the occurrence of tumor heterogeneity. Therefore, the heterogeneity of the tumor phenotype is discussed in conjunction with the various immunotherapeutic treatment modalities. In addition to local cytokine production by immune cells and tumor cells, and limited access of either antibodies or immune cells into the tumor, tumor heterogeneity is an important factor that determines the progress of immunotherapy of cancer. Therefore, accurate quantitative methods using antibodies and molecular probes to identify HLA-associated target peptides, tumor-associated antigens and accessory molecules, to predict which patients will have a high probability of responding to treatment, are needed.

Animals↗
PubMed2000

Extensive intra-tumor heterogeneity in primary human glial tumors as a result of locus non-specific genomic alterations.

Genomic changes are a hallmark of the neoplastic process. These range from alterations at specific loci and defined karyotypic changes which influence tumor behavior to generalized alterations exemplified by microsatellite instability. Generalized genomic changes within a tumor would be evidence in favor of the mutator hypothesis which postulates a role for such extensive changes during tumorigenesis. In this report, we have used the DNA fingerprinting technique of randomly amplified polymorphic DNA (RAPD) analysis to study genomic alterations within primary human astrocytic tumors (gliomas) in a locus non-specific manner. The RAPD fingerprinting profile of consecutive segments of tumors 2 mm across was studied; 17 astrocytic (high- and low-grade) tumors were sectioned end to end. Tissue from 50 consecutive sections, 40 microm thick (total 2 mm across), was pooled and taken to be a tumor compartment. DNA was subjected to RAPD amplification by 15 random 10-mer primers. A tumor segment was taken to have a DNA fingerprinting pattern different from others in the same specimen when its RAPD profile differed from others by at least one band of one RAPD reaction. All but one of the tumors showed compartments with a unique genetic profile, indicating genomic instability leading to widespread intra-tumor genetic heterogeneity. Eight tumors were also studied for loss of heterozygosity (LOH) of the p53 and D17S379 loci in the different segments as examples of alteration of specific tumor influencing loci. Three showed LOH of p53, which was limited to only one compartment of each tumor. The extensive intra-tumor genetic instability detected in this study is suggestive of the overall high rate of change in the genomes of tumors including those of a lower grade. It is hypothesized that some of these altered clones, which manifest as zones of heterogeneity in a solid tumor, may accumulate changes at loci known to influence tumor behavior, and thus clinical outcome.

Brain Neoplasms↗
PubMed1993

Evidence of tumor heterogeneity in cervical cancers and lymph node metastases as determined by flow cytometry.

BACKGROUND: The incidence and significance of tumor heterogeneity in primary tumors and metastatic lymph nodes were investigated in Stage IB-IIA cervical cancers. METHODS: Paraffin-embedded tissues from 96 radical hysterectomy specimens were dewaxed, disaggregated, and subjected to dual parameter flow cytometry. Three-dimensional histograms were generated to delineate different tumor populations. A DNA index difference of at least +/- 0.15 was used to define tumor heterogeneity. RESULTS: Mean DNA index difference of various tumor populations was 0.29 +/- 0.13. Among 69 patients with normal lymph nodes, there were 12 patients (incidence, 17.4%) with tumor heterogeneity in the primary tumors. Of 27 patients with metastatic lymph nodes, 5 (incidence, 18.5%) had evidence of tumor heterogeneity in the primary tumor, and 18 of 47 (incidence, 38.3%) had tumor heterogeneity in metastatic lymph nodes. When using DNA index to determine clonal origin of metastatic lymph nodes, as many as 60% of the metastases could not be traced to the primary tumor. Tumor heterogeneity was associated with a 40% reduction in median survival time. However, because of the small number of patients with tumor heterogeneity, statistical analyses did not show prognostic significance. CONCLUSIONS: Tumor heterogeneity appeared to be a common characteristic of early cervical carcinoma. Additional study is needed to fully evaluate its prognostic value.

Adenocarcinoma↗
PubMed2003

Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry.

Most lung tumor linkage studies focus on identifying loci that confer susceptibility or resistance irrespective of the tumor types developed. However, different mouse strains develop different types of lung tumors. A major obstacle for genetic studies of these differences is the lack of reproducible, quantitative, and uniform assessment of tumor type. We have previously described a new variable (Rratio) that assesses the three-dimensional shape of lung tumors in a quantifiable way and showed that nonspherical tumors are correlated with tumor heterogeneity and with a tendency to asymmetrical growth (N. Tripodis and P. Demant, Exp. Lung Res., 27: 521-531, 2001). In the present study, we use the Rratio variable to search for quantitative trait loci affecting tumor phenotype. We tested the F(2) cross between the susceptible strain O20 and the recombinant congenic strain OcB-9. Both develop mixed alveolar and papillary lung tumors, and the OcB9 tumors are, on average, more elongated than the O20 ones. We mapped eight new lung tumor shape-determining loci (Ltsd1-8) involved in mutual interactions. Two of these loci, Ltsd1 and Ltsd3, seem to play a major role in tumor shape formation. The Ltsd4 locus was confirmed in a second F(2) cross between strain O20 and the recombinant congenic strain OcB-6. Genotype-phenotype associations show that nonspherical tumors are correlated with tumor heterogeneity and nonsymmetrical (focal) development of structures. Most of the new Ltsd loci map in regions where susceptibility to lung cancer (Sluc) loci have been previously mapped, raising the question of whether they are identical or closely linked loci. Based on models of tumor growth indicating that supply of nutrients and the ability to create a capillary network may be shape-determining factors (G. P. Pescarmona et al., Med. Hypoth., 53: 497-503, 1999), we suggest as likely candidates for the Ltsd loci genes involved in angiogenesis, vascularization, and capillary patterning. This is the first set of loci that affects qualitative aspects of lung tumors and may provide biologically and clinically interesting indicators of lung tumor progression.

Animals↗
PubMed2001

Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 AND beta-catenin.

Most hepatocellular carcinomas (HCCs) first occur as well-differentiated HCCs, from which poorly differentiated HCC cells develop because of dedifferentiation. In this study, we try to clarify the changes of dedifferentiation and cell proliferative activity and their relationship in small HCCs (less than 3.0 cm in diameter) and try to learn the mechanism of these changes by analysing the expressions and genetic changes of proliferation-related genes p53 and beta-catenin. Of 41 surgically resected small HCCs, 11 were identified to have tumor heterogeneity. DNA from the 11 small HCCs, consisting of 29 intratumoral lesions and 11 noncancerous liver tissues adjacent to HCCs, was extracted from paraffin embedded tissue sections. Exons 5-8 of p53 gene and exon 3 of beta-catenin gene were amplified by polymerase chain reaction and analyzed by direct sequence. The serial sections were also immunostained by anti-Ki-67, p53 and beta-catenin antibody. Immunohistochemistry showed that the p53 overexpression was significantly related to the proliferative activities as evaluated by Ki-67 immunostaining and to the histological differentiation. The expression of beta-catenin was found to be heterogeneously distributed not only in various histological grades of the same tumor but also in areas of the same histological grade. p53 and beta-catenin gene mutations were detected in 1 tumor respectively, both of which were second primary HCCs and also recurred later. The p53 mutation showed the same mutation pattern in heterogeneous subpopulations. beta-catenin mutation was detected only in the less differentiated lesion but not in the well-differentiated lesion of tumor. In conclusion, our findings suggest that there was histological heterogeneity in small but established HCC, which was accompanied by increased proliferative activity and p53 overexpression. The overexpression of beta-catenin may be related to the proliferative activity and dedifferentiation of HCC.

Aged↗
PubMed1990

Tumor radiocurability: relationship to intrinsic tumor heterogeneity and to the tumor bed effect.

Recent in vitro clonogenic assays of cells from human head and neck carcinomas recurring after fractionated irradiation showed that the mean radiation resistance was significantly greater than that of cells from unirradiated head and neck cancers. Analysis of these data using the linear-quadratic formalism of radiation inactivation indicates that such increased resistance was associated with a large decrease in the parameter describing cell killing by one-hit processes, while the parameter describing cell inactivation by two-hit processes was unchanged. These data suggest that head and neck carcinomas contained intrinsically radioresistant tumor subpopulations that were selected for during the fractionated radiation therapy. Consequently, we have generated a model of how the phenomenon of clonal intraneoplastic diversity might be related to the selection of radioresistant sub-populations. There is, however, an additional major modulating factor which may impact upon the proposed selection process, known as the tumor bed effect. This effect refers to the fact that solid tumors grow at slower rates and to decreased carrying capacities in radiation-damaged normal tissue stroma. We hypothesize that the tumor bed effect is a reflection of an altered, hostile microenvironment within which competition among neoplastic subpopulations for limited resources is increased. This then produces a situation leading to extinction of minority subpopulations within heterogeneous neoplasms, regardless of whether such populations are radioresistant. The final result of these selection/extinction processes will be dependent upon total dose, dose per fraction, overall time, and the initial partial volume percentages of radioresistant subpopulations.

Flow Cytometry↗
PubMed2000

Evaluation of tumor heterogeneity of prostate carcinoma by flow- and image DNA cytometry and histopathological grading.

BACKGROUND: Heterogeneity of prostate carcinoma is one of the reasons for pretreatment underestimation of tumor aggressiveness. We studied tumor heterogeneity and the probability of finding the highest tumor grade and DNA aneuploidy with relation to the number of biopsies. MATERIAL AND METHODS: Specimens simulating core biopsies from five randomly selected tumor areas from each of 16 Böcking's grade II and 23 grade III prostate carcinomas were analyzed for tumor grade and DNA ploidy by flow- and fluorescence image cytometry (FCM, FICM). Cell cycle composition was measured by FCM. RESULTS: By determination of ploidy and cell cycle composition, morphologically defined tumors can further be subdivided. Heterogeneity of tumor grade and DNA ploidy (FCM) was 54% and 50%. Coexistence of diploid tumor cells in aneuploid specimens represents another form of tumor heterogeneity. The proportion of diploid tumor cells decreased significantly with tumor grade and with increase in the fraction of proliferating cell of the aneuploid tumor part. The probability of estimating the highest tumor grade or aneuploidy increased from 40% for one biopsy to 95% for 5 biopsies studied. By combining the tumor grade with DNA ploidy, the probability of detecting a highly aggressive tumor increased from 40% to 70% and 90% for one and two biopsies, respectively. CONCLUSION: Specimens of the size of core biopsies can be used for evaluation of DNA ploidy and cell cycle composition. Underestimation of aggressiveness of prostate carcinoma due to tumor heterogeneity is minimized by simultaneous study of the tumor grade and DNA ploidy more than by increasing the number of biopsies. The biological significance of coexistent diploid tumor cell in aneuploid lesions remains to be evaluated.

Biopsy↗
PubMed1980

The generation of tumor heterogeneity in vivo.

In order to determine whether host factors may contribute to the generation of tumor heterogeneity, the phenotypic stability of cells from a cloned tumor was examined during proliferation in tissue culture and in the syngeneic host. Growth of this cloned tumor was initiated both in vivo and in vitro, and the tumor populations were sampled at different time intervals by subcloning. The susceptibility of these tumor subclones to the cytotoxic action of natural antibodies and complement was used as a marker of their membrane phenotype. The extent of phenotypic variation of the clones in one sample was considered to be a measure of tumor heterogeneity. Following these procedures, we observed that a clone of the L5178Y murine lymphoma maintained its homogeneity during 5 months of in vitro culture. In contrast, a single passage of the same tumor clone for 3 1/2 weeks or 3 months in the syngeneic host resulted in the generation of a population of cells exhibiting a significant increase in heterogeneity. This relative instability of tumor phenotype in vivo suggests that the host milieu may allow the generation of tumor heterogeneity. Genetic or epigenetic mechanism(s) may be involved although the high frequency of new phenotypes argues against a role for somatic mutation.

Animals↗
PubMed2001

Three-dimensional patterns of lung tumor growth: association with tumor heterogeneity.

Most histological Classifications of lung tumors assess information derived from 2-dimensional surfaces. However, tumors grow in 3 dimensions in a variety of architectural patterns that possibly reflect the histological type or progresssion status of the tumor. A new mathematically derived variable (Rratio) is presented, that assesses the overall 3-dimensional shape of a tumor and classifies tumors based on their sphericality. Analysis and comparison of groups of spherical and nonspherical tumors from mouse inbred strains and recombinant congenic strains with a strict set of predetermined histological criteria shows that Rratio is significantly associated with tumor heterogeneity and that histological differences exist between the spherical and nonspherical tumors. These results suggest that Rratio may be a valuable tool for the characterization of tumors and can be used to explore qualitative differences in tumors derived from segregating crosses.

Adenoma↗
PubMed1989

Therapeutic implications of tumor heterogeneity.

At the outset of this review, we stated that we wished to raise some questions that challenge the commonly held view that tumor heterogeneity is of major significance to treatment failure. The nature of this challenge is the following: although tumor heterogeneity in sensitivity to therapeutic agents has been demonstrated repeatedly, using isolated subpopulations of cells, primarily in cell culture systems, there is very little work that has been directed toward asking the tough questions about how that heterogeneity actually impacts on the response to treatment in vivo. In our own work, when we have attempted to simulate heterogeneity, in vivo or in vitro with mixed populations of tumor cells, we have seen that the simple prediction that treatment response would reflect the sensitivities of the individual subpopulations was not valid. Tumor subpopulation interactions, influencing both growth and drug sensitivity, resulted in treatment responses that were either better or worse than would be expected. Shifts in the distribution of subpopulations under the influence of therapy did not necessarily correlate with treatment response. Marked differences in the relative proportions of subpopulations within tumors did not necessarily translate into marked differences in the behavior of whole tumors. Imposition of in vivo-like three-dimensional tissue architecture caused major changes in the overall drug sensitivity of individual subpopulations, beyond those seen as a result of heterogeneity. Of course we realize that our work is very limited, one tumor system and a few treatment protocols, but that is the challenge. Much more in-depth experimental and clinical research is necessary in order to evaluate how, and how much, tumor heterogeneity really does affect treatment. Without such work, efforts to devise more effective treatment strategies, based on common assumptions and theoretical models, rather than experimental analysis, can only be superficial and, ultimately, useless.

Animals↗
PubMed1989

Stochastic models for subpopulation emergence in heterogeneous tumors.

A stochastic analog to a deterministic model describing subpopulation emergence in heterogeneous tumors is developed. The resulting system is described by the Fokker-Planck or forward Kolmogorov equation. A finite element approach for the numerical solution to this equation is described. Four biological and clinical scenarios are simulated (emergence of heterogeneity, exclusion of a subpopulation, and induction of drug resistance in both pure and heterogeneous tumors). The results of the simulations show that the stochastic model describes the same basic dynamics as its deterministic counterpart via a convective component, but that for each simulation a distribution of tumor sizes and mixes can also be derived from a diffusive component in the model. These distributions yield estimates for subpopulation extinction probabilities. The biological and clinical relevance of these results are discussed.

Drug Resistance↗