Tumor Heterogeneity

Heppner, Gloria H.; Shapiro, William R.; Rankin, J. K.

doi:10.1007/978-94-009-8219-2_4

Cited by 165 publications

(185 citation statements)

References 45 publications

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“…Further divergence of the clone may result in subpopulations of neoplastic cells, some of which gain the capacity to metastasize. [13][14][15][16][17] Although genetic heterogeneity is the norm in melanoma, [18][19][20][21][22] it would be expected that a primary melanoma and its metastases would share at least one or more genetic alterations. Studies to date have shown that loss of heterozygosity (LOH) on 9p and 10q has been associated with early-stage primary disease, whereas LOH on 6q, 1p, 8q, and 11q has been associated with progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

et al. 2007

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Loss of heterozygosity (LOH) has previously been demonstrated at multiple chromosome microsatellites in primary and metastatic melanomas. Epidermotropic metastases of melanoma are unique in their varied histopathologic appearance, which can mimic a primary lesion. Our objective was to compare LOH profiles in primary and epidermotropic metastatic melanoma to delineate their clonal relationship. We examined the pattern of allelic loss in the primary melanomas of nine patients in addition to the 21 corresponding epidermotropic metastatic melanomas (average 2.3 metastases per patient). DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser capture microdissection. Eight DNA microsatellite markers on six different chromosomes were analyzed: D1S214 (1p), D6S305 (6q), D9S171 (9p), D9S157 (9p), IFNA (9p), D10S212 (10q), D11S258 (11q), D18S70 (18q). In addition, X-chromosome inactivation analysis was performed in tumors from four women. LOH was seen in 67% (6/9) of primary melanomas and 81% (17/21) of epidermotropic metastatic melanomas. The most frequent allelic losses in informative cases occurred at 10q (33%), 9p (22%), and 11q (22%) in primary melanomas, and at 10q (50%), 1p (44%), and 6q (39%) in epidermotropic metastatic melanomas. Primary lesions demonstrating LOH had concordant allelic loss in at least one locus in a corresponding epidermotropic metastatic melanoma in 83% (5/6) of cases. X-chromosome analysis showed nonrandom inactivation in 75% (3/4) and 71% (5/7) of primary melanoma and epidermotropic metastatic melanoma cases, respectively. Our LOH and X-chromosome inactivation analysis data suggest that epidermotropically metastatic melanomas are clonally related to their primary lesion in many cases. Our data also indicated that some cases diagnosed as epidermotropic metastatic melanoma might be divergent clones or new primaries rather than metastatic disease.

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Section: Introductionmentioning

confidence: 99%

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

et al. 2007

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“…1 The term "tumor heterogeneity" is used to define the appearance of different histological differentiation within a single neoplasm. 2 Some investigators suggest that such heterogeneity was related to multistep genetic alterations. 3,4 Analysis of the genetic alterations in tumors with the heterogeneity, therefore, should be beneficial to determine their roles in tumor progression.…”

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confidence: 99%

Tumor heterogeneity in small hepatocellular carcinoma: Analysis of tumor cell proliferation, expression and mutation of p53 AND ?-catenin

Matsuda

Fujii

et al. 2001

Int. J. Cancer

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Most hepatocellular carcinomas (HCCs) first occur as welldifferentiated 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 ␤-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 ␤-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 ␤-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 ␤-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 ␤-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. ␤-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 ␤-catenin may be related to the proliferative activity and dedifferentiation of HCC.

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“…These aspects can exert a significant influence on the response of tumor cells to therapy (13,151. Moreover, by the time of diagnosis, and certainly in clinically advanced lesions, malignant neoplasms and metastases contain multiple cell populations exhibiting a wide range of biological heterogeneity in such parameters as cell surface properties, antigenicity, immunogenicity, growth rate, karyotype, sensitivity to various cytotoxic drugs, and the ability to invade and metastasize (6,13,15,22,38,39,62,70). This biological heterogeneity presents a major obstacle to effective therapy.…”

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Origin and biology of cancer metastasis

Fidler

1989

Cytometry

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Metastasis, the spread of cells from a primary neoplasm to distant sites where they grow, contributes to the death of most cancer patients. The process of metastasis is not random. Rather, the process consists of a series of linked, sequential steps that must be completed by tumor cells if a metastasis is to develop. Thus, metastatic cells must succeed in invasion and embolization, survive in the circulation, arrest in a distant capillary bed, and extravasate into and multiply in organ parenchyma. Although some of the steps in this process contain stochastic elements, as a whole metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Moreover, metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with different organ environments. Organ-specific metastases have been demonstrated in a variety of experimental tumor systems, and even within one organ, site-specific tumor growth can be found.The conclusion that metastasis is a highly selective process that is influenced by both the intrinsic properties of tumor cells and by host factors is optimistic. A selective process is regulated and therefore can be studied and then manipulated.Key terms: Metastasis, selective, stochastic, organ selectivityThe ability of malignant neoplasms to produce secondary growths (metastases) in organs distant from the primary tumors is the lethal event in the clinical course of most neoplastic diseases. While primary cancers can be surgically resected or locally irradiated, it is usually difficult to use these therapeutic modalities against disseminated disease. In the majority of patients, by the time of diagnosis of primary malignant neoplasms (excluding skin cancers), metastasis may well have occurred (13,15,71,94,96,99). Metastases can be located in different organs and in different anatomical locations within the same organ. These aspects can exert a significant influence on the response of tumor cells to therapy (13,151. Moreover, by the time of diagnosis, and certainly in clinically advanced lesions, malignant neoplasms and metastases contain multiple cell populations exhibiting a wide range of biological heterogeneity in such parameters as cell surface properties, antigenicity, immunogenicity, growth rate, karyotype, sensitivity to various cytotoxic drugs, and the ability to invade and metastasize (6,13,15,22,38,39,62,70). This biological heterogeneity presents a major obstacle to effective therapy.Continual empiricism in the treatment of cancer metastasis is unlikely to produce improvements. Understanding the mechanisms responsible for the origin, establishment, and growth of cancer metastases and for the development of biological heterogeneity in metastases should contribute to improvements in the design of more effective therapy and in the way physicians deal with cancer metastasis. This brief review concerns data that provide a few a...

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Tumor Heterogeneity

Cited by 165 publications

References 45 publications

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

Tumor heterogeneity in small hepatocellular carcinoma: Analysis of tumor cell proliferation, expression and mutation of p53 AND ?-catenin

Origin and biology of cancer metastasis

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