Tumor heterogeneity: biological implications and therapeutic consequences

The Clonal Evolution of Tumor Cell Populations: Acquired genetic lability permits stepwise selection of variant sublines and underlies tumor progression.

Nowell, P. C. (1976) · Science · doi:10.1126/science.959840 · Cited by 6,471

Mutations of bacteria from virus sensitivity to virus resistance

Luria, S. E., & Delbrück, M. (1943) · Genetics · doi:10.1093/genetics/28.6.491 · Cited by 3,894

Growth factors from murine sarcoma virus-transformed cells.

de Larco, J. E., & Todaro, G. J. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.8.4001 · Cited by 1,461

Metastasis Results from Preexisting Variant Cells Within a Malignant Tumor

Fidler, I. J., & Kripke, M. L. (1977) · Science · doi:10.1126/science.887927 · Cited by 1,425

DQIS — Distributed Quorum-Based Independent Immune Surveillance: A Theoretical Framework for Byzantine Fault Tolerance for Multi-Channel Immune Surveillance

DQIS Research Group (2026) · PubMed · doi:10.5281/zenodo.21937949 · Cited by 1,327

Quantitation of Differential Sensitivity of Human-Tumor Stem Cells to Anticancer Drugs

Salmon, S. E., Hamburger, A. W., Soehnlen, B., Durie, B. G. M., Alberts, D. S., & Moon, T. E. (1978) · New England Journal of Medicine · doi:10.1056/nejm197806152982401 · Cited by 970

Junctional intercellular communication and the control of growth

Loewenstein, W. R. (1979) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(79)90002-7 · Cited by 957

Clonal origin of human tumors

FIALKOW, P. (1976) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(76)90003-2 · Cited by 647

Heterogeneity of tumor cells from a single mouse mammary tumor.

Dexter, D. L., Kowalski, H. M., Blazar, B. A., Fligiel, Z., Vogel, R., & Heppner, G. H. (1978) · PubMed · Cited by 579

High Levels of Intracellular Bombesin Characterize Human Small-Cell Lung Carcinoma

Moody, T. W., Pert, C. B., Gazdar, A. F., Carney, D. N., & Minna, J. D. (1981) · Science · doi:10.1126/science.6272398 · Cited by 487

Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma.

Isaacs, J. T., & Coffey, D. S. (1981) · PubMed · Cited by 371

Hemopoietic stem cell differentiation

Till, J. E., & McCulloch, E. A. (1980) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(80)90009-8 · Cited by 340

Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma.

Vaupel, P. W., Frinak, S., & Bicher, H. I. (1981) · PubMed · Cited by 337

Metabolic co-operation between biochemically marked mammalian cells in tissue culture

Subak-Sharpe, H., Bürk, R. R., & Pitts, J. D. (1969) · Journal of Cell Science · doi:10.1242/jcs.4.2.353 · Cited by 328

Tumor Shedding and Coagulation

Dvorak, H. F., Quay, S. C., Orenstein, N. S., Dvorak, A. M., Hahn, P., Bitzer, A. M., & Carvalho, A. C. (1981) · Science · doi:10.1126/science.7195067 · Cited by 302

Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells.

Poste, G., Doll, J., & Fidler, I. J. (1981) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.78.10.6226 · Cited by 301

Neoplastic Development

Lendrum, A. C. (1970) · Journal of Clinical Pathology · doi:10.1136/jcp.23.3.278-a · Cited by 292

Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms.

Cifone, M. A., & Fidler, I. J. (1981) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.78.11.6949 · Cited by 289

Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas.

Shapiro, J. R., Yung, W. K. A., & Shapiro, W. R. (1981) · PubMed · Cited by 285

Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor.

Heppner, G. H., Dexter, D. L., DeNucci, T., Miller, F. R., & Calabresi, P. A. (1978) · PubMed · Cited by 280

Endomitotic Reduplication Mechanisms in Ascites Tumors of the Mouse 2

(1953) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/14.1.1 · Cited by 279

Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability.

Miller, F. R., Miller, B. E., & Heppner, G. H. (1983) · PubMed · Cited by 262

Mutation Caused by Human Phagocytes

Weitzman, S. A., & Stossel, T. P. (1981) · Science · doi:10.1126/science.6259738 · Cited by 260

Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin.

Kripke, M. L., Gruys, E., & Fidler, I. J. (1978) · PubMed · Cited by 247

Proliferation-dependent cytotoxicity of anticancer agents: a review.

Valeriote, F. A., & van Putten, L. (1975) · PubMed · Cited by 214

Heterogeneity in surface antigen and glycoprotein expression of cell lines derived from different melanoma metastases of the same patient. Implications for the study of tumor antigens.

Albino, A. P., Lloyd, K. O., Houghton, A. N., Oettgen, H. F., & Old, L. J. (1981) · The Journal of experimental medicine · doi:10.1084/jem.154.6.1764 · Cited by 207

Specificity of arrest, survival, and growth of selected metastatic variant cell lines.

Nicolson, G. L., Brunson, K. W., & Fidler, I. J. (1978) · PubMed · Cited by 204

Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis.

Ogawa, K., Solt, D. B., & Farber, E. (1980) · PubMed · Cited by 199

Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin.

Fidler, I. J., Gruys, E., Cifone, M. A., Barnes, Z., & Bucana, C. D. (1981) · PubMed · Cited by 194

Clonal Origin of Human Tumors

Fialkow, P. J. (1979) · Annual Review of Medicine · doi:10.1146/annurev.me.30.020179.001031 · Cited by 189

Clonal heterogeneity of small-cell anaplastic carcinoma of the lung demonstrated by flow-cytometric DNA analysis.

Vindeløv, L. L., Hansen, H. H., Christensen, I. J., Spang‐Thomsen, M., Hirsch, F. R., Hansen, M., & Nissen, N. I. (1980) · PubMed · Cited by 174

Heterogeneity of cancer cells from a single human colon carcinoma

Dexter, D. L., Spremulli, E. N., Fligiel, Z., Barbosa, J. A., Vogel, R., VanVoorhees, A., & Calabresi, P. (1981) · The American Journal of Medicine · doi:10.1016/0002-9343(81)90312-0 · Cited by 168

Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R-3327 rat prostatic adenocarcinoma system.

Isaacs, J. T., Wake, N., Coffey, D. S., & Sandberg, A. A. (1982) · PubMed · Cited by 165

FURTHER EVIDENCE FAVORING THE CONCEPT OF THE STEM CELL IN ASCITES TUMORS OF RATS

Makino, S. (1956) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1956.tb50894.x · Cited by 152

Immunological resistance to pulmonary metastases in C3Hf-Bu mice bearing syngeneic fibrosarcoma of different sizes.

Milas, L., Hunter, N. R., Mason, K. A., & Withers, H. R. (1974) · PubMed · Cited by 150

Differences in drug sensitivity among tumor cells from parental tumors, selected variants, and spontaneous metastases.

Tsuruo, T., & Fidler, I. J. (1981) · PubMed · Cited by 142

Phenotypic drift of metastatic and cell‐surface properties of mammary adenocarcinoma cell clones during growth in vitro

Neri, A., & Nicolson, G. L. (1981) · International Journal of Cancer · doi:10.1002/ijc.2910280612 · Cited by 139

Analysis of Antigenic Heterogeneity Within Individual 3-Methylcholanthrene-Induced Mouse Sarcomas 2

Prehn, R. T. (1970) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/45.5.1039 · Cited by 125

Origin of the Resistance of Leukæmic Cells to Folic Acid Antagonists

Law, L. W. (1952) · Nature · doi:10.1038/169628a0 · Cited by 117

Comparison of the metastatic properties of B16 melanoma clones isolated from cultured cell lines, subcutaneous tumors, and individual lung metastases.

Poste, G. H., Doll, J., Brown, A. E., Tzeng, J., & Zeidman, I. (1982) · PubMed · Cited by 103

Multicellular origin of fibrosarcomas in mice induced by the chemical carcinogen 3-methylcholanthrene.

Reddy, A. L., & Fialkow, P. (1979) · The Journal of Experimental Medicine · doi:10.1084/jem.150.4.878 · Cited by 95

GROWTH OF A LOCAL TUMOR EXERTS A SPECIFIC INHIBITORY EFFECT ON PROGRESSION OF LUNG METASTASES

Gorelik, E., Segal, S., & Feldman, M. (1978) · International Journal of Cancer · doi:10.1002/ijc.2910210512 · Cited by 94

The chromosomes of fifty primary Rous rat sarcomas

Mitelman, F. (2009) · Hereditas · doi:10.1111/j.1601-5223.1971.tb02431.x · Cited by 94

Detection of inapparent nodule-transformed cells in the mammary gland tissues of virgin female BALB/cfC3H mice.

DeOme, K. B., Miyamoto, M. J., Osborn, R. C., Guzman, R. C., & Lum, K. (1978) · PubMed · Cited by 89

The variability of estrogen receptors in metastatic breast cancer

Brennan, M. J., Donegan, W. L., & Appleby, D. E. (1979) · The American Journal of Surgery · doi:10.1016/0002-9610(79)90159-4 · Cited by 88

Commentaries on research in breast disease

Bulbrook, R. D., & Taylor, D. J. (1983) · Medical Entomology and Zoology · Cited by 85

Biological and experimental consequences of the zonal composition of solid tumors.

Fidler, I. J., & Hart, I. R. (1981) · PubMed · Cited by 78

Restriction enzyme analysis of mouse cellular type C viral DNA: emergence of new viral sequences in spontaneous AKR/J lymphomas.

Canaani, E., & Aaronson, S. A. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.4.1677 · Cited by 74

A critical analysis of tumor morphology and hormone treatments in the untreated and estrogen-treated responsive and refractory human prostatic carcinoma

Sinha, A. A., Blackard, C. E., & Seal, U. S. (1977) · Cancer · Cited by 69

Apparent reversion of stable in vitro genetic markers detected in tumour cells from spontaneous metastases

Dennis, J. W., Donaghue, T. P., Florian, M., et al. (1981) · Nature · doi:10.1038/292242a0 · Cited by 64

Is Somatic Mutation the Major Mechanism of Malignant Transformation?

Rubin, H. (1980) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/64.5.995 · Cited by 61

Characterization of tumor lines derived from spontaneous metastases of a transplanted murine sarcoma

Mantovani, A., Giavazzi, R., Alessandri, G., Spreafico, F., & Garattini, S. K. (1981) · European Journal of Cancer (1965) · doi:10.1016/0014-2964(81)90213-9 · Cited by 58

The inhibitory influence of a transplanted hamster lymphoma on metastasis.

Greene, H. S. N., & Harvey, E. K. (1960) · PubMed · Cited by 55

Enhancement of the Tumorigenicity of Preneoplastic Mammary Nodule Lines by Enzymatic Dissociation2

Medina, D. J., Shepherd, F., & Gropp, T. (1978) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/60.5.1121 · Cited by 53

Isolation of a cellular subpopulation from a human colonic carcinoma cell line.

KIMBALL, P. M., & Brattain, M. G. (1980) · PubMed · Cited by 52

Characterization of primary hepatocellular carcinomas and initial transplant generations.

Becker, F., Klein, K. M., Wolman, S. R., Asofsky, R., & Sell, S. (1973) · PubMed · Cited by 51

Intratumor immunologic heterogeneity

Miller, F. R. (1982) · Cancer and Metastasis Reviews · doi:10.1007/bf00124215 · Cited by 50

An approach to the problem of heterogeneity of human tumour-cell populations

Siracký, J. (1979) · British Journal of Cancer · doi:10.1038/bjc.1979.103 · Cited by 50

Inhibition of subcutaneously growing line 1 carcinomas due to metastatic spread.

Yuhas, J. M., & Pazmiño, N. H. (1974) · PubMed · Cited by 49

On the mechanism of tumor ‘concomitant immunity’

Gorelik, E., Segal, S., & Feldman, M. (1981) · International Journal of Cancer · doi:10.1002/ijc.2910270618 · Cited by 49

Evidence for single-cell origin of 3-methylcholanthrene-induced fibrosarcomas in mice with cellular mosaicism.

Tanooka, H., & Tanaka, K. (1982) · PubMed · Cited by 42

Variation in steroid 5 alpha-reductase activity in cloned human skin fibroblasts. Shift in phenotypic expression from high to low activity upon subcloning.

Griffin, J. E., Allman, D. R., Durrant, J. L., & Wilson, J. D. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)69504-9 · Cited by 38

Cell-Cycle Dependent Appearance of Murine Leukemia-Sarcoma Virus Antigens

Panem, S., & Schauf, V. (1974) · Journal of Virology · doi:10.1128/jvi.13.6.1169-1175.1974 · Cited by 36

Viral “Tumorigenesis” in man: Cell markers in condylomata acuminata

Friedman, J. M., & Fialkow, P. J. (1976) · International Journal of Cancer · doi:10.1002/ijc.2910170109 · Cited by 34

Immunotherapy with tumor cell subpopulations

Killion, J. (1978) · Cancer Immunology Immunotherapy · doi:10.1007/bf00200112 · Cited by 20

Development and characterization of mouse hyperplastic mammary outgrowth lines from BALB/cfC3H hyperplastic alveolar nodules.

Ashley, R. L., Cardiff, R. D., Mitchell, D. J., Faulkin, L. J., & Lund, J. K. (1980) · PubMed · Cited by 20

Untitled work

(1981) · PubMed

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

Visvader, J. E., & Lindeman, G. J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2499 · Cited by 3,429

Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment

Barkley, D., Moncada, R., Pour, M., Liberman, D. A., Dryg, I., Werba, G., Wang, W., Baron, M., Rao, A., Xia, B., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01141-9 · Cited by 532

Translational Implications of Tumor Heterogeneity

Jamal-Hanjani, M., Quezada, S. A., Larkin, J., & Swanton, C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1429 · Cited by 549

Cellular Heterogeneity and Molecular Evolution in Cancer

Almendro, V., Marusyk, A., & Polyak, K. (2013) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163923 · Cited by 498

Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity?

Albino, A. P., Strange, R. L., Oliff, A. I., Furth, M. E., & Old, L. J. (1984) · Nature · doi:10.1038/308069a0 · Cited by 324