Tumor reversion: Correction of malignant behavior by microenvironmental cues

Cancer is characterized by unrestrained proliferation and loss of organization, a process that is intimately linked to, and controlled by, reciprocal signaling between the genetically altered tumor epithelium, the stroma, the components of the basement membrane and inflammatory mediators. Much work has been done to characterize the genetics of cancer cells. In this review, we describe the experiments that have been performed, which point to the significant role of the tissue microenvironment in the developmental regulation of normal and neoplastic cells. Using a variety of model systems, the works of a number of laboratories have converged on a hypothesis where the correction of 1 or 2 signaling defects can revert tumor cells to a normal phenotype, both in vivo and in culture, even when the tumor cells possess multiple genetic and epigenetic lesions. This paradigm has been successfully used to treat acute promyelocytic leukemia, and it remains the task of biomedical researchers to identify additional targets for the reversion of other human malignancies. © 2003 Wiley‐Liss, Inc.

[1]  J. Pipas,et al.  Transforming functions of Simian Virus 40 , 2001, Oncogene.

[2]  Mina J Bissell,et al.  The organizing principle: microenvironmental influences in the normal and malignant breast. , 2002, Differentiation; research in biological diversity.

[3]  C. Larabell,et al.  Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies , 1997, The Journal of cell biology.

[4]  R. Weinberg,et al.  Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Bissell,et al.  Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata , 1984, The Journal of cell biology.

[7]  M J Bissell,et al.  The embryonic environment strongly attenuates v-src oncogenesis in mesenchymal and epithelial tissues, but not in endothelia , 1990, The Journal of cell biology.

[8]  M. Sporn,et al.  Transforming growth factor-beta: biological function and chemical structure. , 1986, Science.

[9]  M. Bissell,et al.  Division of labor among the alpha6beta4 integrin, beta1 integrins, and an E3 laminin receptor to signal morphogenesis and beta-casein expression in mammary epithelial cells. , 2011, Molecular biology of the cell.

[10]  Mina J Bissell,et al.  Modeling tissue-specific signaling and organ function in three dimensions , 2003, Journal of Cell Science.

[11]  H. Moses,et al.  Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. , 1984, Science.

[12]  G. B. Pierce,et al.  MULTIPOTENTIALITY OF SINGLE EMBRYONAL CARCINOMA CELLS. , 1964, Cancer research.

[13]  M. Bissell.  The differentiated state of normal and malignant cells or how to define a "normal" cell in culture. , 1981, International review of cytology.

[14]  R. DePinho,et al.  Use of the human EF-1alpha promoter for expression can significantly increase success in establishing stable cell lines with consistent expression: a study using the tetracycline-inducible system in human cancer cells. , 1999, Nucleic acids research.

[15]  M J Bissell,et al.  How does the extracellular matrix direct gene expression? , 1982, Journal of theoretical biology.

[16]  F. Duran-Reynals,et al.  Growth of a Chicken Sarcoma Virus in the Chick Embryo in the Absence of Neoplasia , 1943 .

[17]  R. Cardiff,et al.  Mammary epithelial-specific expression of the integrin linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice , 2001, Oncogene.

[18]  D. Felsher,et al.  Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. , 2003, Blood.

[19]  S. Minucci,et al.  Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia , 1998, Nature.

[20]  C H Streuli,et al.  Laminin mediates tissue-specific gene expression in mammary epithelia , 1995, The Journal of cell biology.

[21]  M J Bissell,et al.  Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. , 1996, Physiological reviews.

[22]  M J Bissell,et al.  A Novel Function for the nm23-Hl Gene: Overexpression in Human Breast Carcinoma Cells Leads to the Formation of Basement Membrane and Growth Arrest , 2010 .

[23]  Mitchell D Schnall,et al.  Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. , 2002, Cancer cell.

[24]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[25]  Mina J Bissell,et al.  Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. , 2010, Journal of cell science.

[26]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[27]  V. Weaver,et al.  Tissue structure, nuclear organization, and gene expression in normal and malignant breast. , 1999, Cancer research.

[28]  P. Vogt,et al.  Differences between the Ribonucleic Acids of Transforming and Nontransforming Avian Tumor Viruses* , 1970, Proceedings of the National Academy of Sciences.

[29]  Martin Gs.  The hunting of the Src. , 2001 .

[30]  Pingfang Liu,et al.  CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. C. Stevens,et al.  Spontaneous Testicular Teratomas in an Inbred Strain of Mice. , 1954, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Sporn,et al.  Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. , 1990, Science.

[33]  F. Salvatore,et al.  BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations , 2002, Oncogene.

[34]  R. Bhatia,et al.  Tyrphostin AG957, a tyrosine kinase inhibitor with anti-BCR/ABL tyrosine kinase activity restores β1 integrin-mediated adhesion and inhibitory signaling in chronic myelogenous leukemia hematopoietic progenitors , 1998, Leukemia.

[35]  W. Michael Korn,et al.  Disruption of 3D tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Bloomfield,et al.  Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide. , 2002, The oncologist.

[37]  C. Conti,et al.  Second symposium of novel molecular targets for cancer therapy. , 2001, The oncologist.

[38]  C. Larabell,et al.  Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M J Bissell,et al.  Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. , 1989, Development.

[40]  Gage Martin.  Rous Sarcoma Virus: a Function required for the Maintenance of the Transformed State , 1970, Nature.

[41]  D. Tenen,et al.  Reversibility of acute B-cell leukaemia induced by BCR–ABL1 , 2000, Nature Genetics.

[42]  Mina J. Bissell,et al.  Putting tumours in context , 2001, Nature Reviews Cancer.

[43]  H. Varmus,et al.  Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. , 2001, Genes & development.

[44]  P. Rous,et al.  A SARCOMA OF THE FOWL TRANSMISSIBLE BY AN AGENT SEPARABLE FROM THE TUMOR CELLS , 1911, Journal of Experimental Medicine.

[45]  M. Bissell,et al.  ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini , 2001, Nature Cell Biology.

[46]  Alan Ashworth,et al.  Retroviral vectors for establishing tetracycline-regulated gene expression in an otherwise recalcitrant cell line , 2002, BMC Molecular Biology.

[47]  Christian A. Rees,et al.  Systematic variation in gene expression patterns in human cancer cell lines , 2000, Nature Genetics.

[48]  L. Chin,et al.  Essential role for oncogenic Ras in tumour maintenance , 1999, Nature.

[49]  M. Santoro,et al.  Cloning and molecular characterization of a novel gene strongly induced by the adenovirus E1A gene in rat thyroid cells , 2003, Oncogene.

[50]  J. Bjorge,et al.  Selected glimpses into the activation and function of Src kinase , 2000, Oncogene.

[51]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[52]  R. Cardiff,et al.  c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations , 2001, Nature Medicine.

[53]  H. Varmus,et al.  DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA , 1976, Nature.

[54]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[55]  M J Bissell,et al.  Cellular growth and survival are mediated by beta 1 integrins in normal human breast epithelium but not in breast carcinoma. , 1995, Journal of cell science.

[56]  K. Campbell,et al.  A role for dystroglycan in epithelial polarization: loss of function in breast tumor cells. , 2002, Cancer research.

[57]  M. Tallman,et al.  Acute promyelocytic leukemia: evolving therapeutic strategies. , 2002, Blood.

[58]  M. Bissell,et al.  Wounding and its role in RSV-mediated tumor formation. , 1985, Science.

[59]  K. Campbell,et al.  Reduced expression of dystroglycan in breast and prostate cancer. , 2001, Human pathology.

[60]  L. Bolund,et al.  Molecular cytogenetic analysis of a nontumorigenic human breast epithelial cell line that eventually turns tumorigenic: Validation of an analytical approach combining karyotyping, comparative genomic hybridization, chromosome painting, and single‐locus fluorescence in situ hybridization , 1997, Genes, chromosomes & cancer.

[61]  M J Bissell,et al.  Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[62]  R. Hansen,et al.  Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. , 2002, Journal of the National Cancer Institute.

[63]  G. Gallia,et al.  Evaluation of an autoregulatory tetracycline regulated system , 1998, Oncogene.

[64]  R. Bhatia,et al.  Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores beta1 integrin-mediated adhesion and proliferation inhibition in chronic myelogenous leukemia hematopoietic progenitors. , 1998, Blood.

[65]  O. Petersen,et al.  Trisomy 7p and malignant transformation of human breast epithelial cells following epidermal growth factor withdrawal. , 1996, Cancer research.

[66]  L. Liotta,et al.  Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. , 1982, Biochemistry.

[67]  G. Martin.  The hunting of the Src , 2001, Nature Reviews Molecular Cell Biology.

[68]  M. Bissell,et al.  Division of Labor among the α6β4 Integrin, β1 Integrins, and an E3 Laminin Receptor to Signal Morphogenesis and β-Casein Expression in Mammary Epithelial Cells , 1999 .

[69]  C. Verfaillie,et al.  Interferon-alpha restores normal beta 1 integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment in chronic myelogenous leukemia. , 1996, Blood.

[70]  M. Bissell,et al.  Inability of Rous sarcoma virus to cause sarcomas in the avian embryo , 1984, Nature.

[71]  J. Tichelaar,et al.  FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[72]  J. Lotem,et al.  Epigenetics wins over genetics: induction of differentiation in tumor cells. , 2002, Seminars in cancer biology.

[73]  J. Downward.  Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[74]  L. Hennighausen,et al.  Time-Sensitive Reversal of Hyperplasia in Transgenic Mice Expressing SV40 T Antigen , 1996, Science.

[75]  R. Brinster.  THE EFFECT OF CELLS TRANSFERRED INTO THE MOUSE BLASTOCYST ON SUBSEQUENT DEVELOPMENT , 1974, The Journal of experimental medicine.

[76]  Kenneth Chu,et al.  Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC , 2002, Science.

[77]  K. Illmensee,et al.  Normal genetically mosaic mice produced from malignant teratocarcinoma cells. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M. Bissell,et al.  The tumor-promoting effect of wounding: a possible role for TGF-beta-induced stromal alterations. , 1994, Critical reviews in oncogenesis.

[79]  P. Steeg,et al.  Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. , 1993, Oncogene.

[80]  M. Bissell,et al.  Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[81]  M. Bissell,et al.  pp60v-src tyrosine kinase is expressed and active in sarcoma-free avian embryos microinjected with Rous sarcoma virus. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[82]  G. Ellison,et al.  Further evidence to support the melanocytic origin of MDA-MB-435 , 2002, Molecular pathology : MP.