F1000-Biology review very well summarized the significance of this paper!
Avri Ben-Ze'ev
Weizmann Institute of Science, Israel
Cell BiologyThis paper demonstrates that we have to re-think, when relating to the key stages in the current models of tumor progression that lead to metastasis, since the authors of this work demonstrate that it is possible to colonize the lung with untransformed mammary epithelial cells (by tail vein injection). Such cells can apparently survive there for several months and, when induced to express certain oncogenes, can produce metastatic lung cancer in mice.
The capacity of tumor cells to form metastases is believed to include a sequence of events occurring at the primary tumor site resulting in the acquisition of invasive potential into neighbouring tissues, followed by intravasation into the blood and/or lymphatic systems and extravasation at distal sites, where new colonies of tumour cells develop. This process is believed to be highly inefficient, with only very few cells being able to complete the entire process resulting in the formation of metastases. The paper by Podsypanina et al. makes us re-think whether it is necessary for cancer cells to be associated with the primary tumor in order to produce metastases. The authors have injected into the tail vein of mice mammary epithelial cells defined as normal, except for their capacity to inducibly express various oncogenes. They demonstrate that such cells (after being trapped in the lung) can survive there for several weeks and, when induced to express various oncogenes, will produce metastatic lung cancer. Thus, by eliminating the intravasation and extravasation step, these studies raise a variety of novel and provocative questions, including whether there is a requirement for several rounds of cell division for genetic changes at the primary tumor site that will lead to the development of the invasive metastatic capacity, as well as whether normal cells can routinely disseminate and reside in distal tissues, and, finally, how such cells can become tumorigenic-metastatic at these distal sites.
There are several reviews on F1000-Medicine as well.
Larry Suva
University of Arkansas Medical Sciences, United States of America
Rheumatology & Clinical ImmunologyPodsypanina and co-workers shift the metastasis paradigm toward one that suggests our understanding of the sequence of events leading to tumor progression may not be accurate.
It has long been considered ‘lore’ that the metastatic growth of cancer is the final stage in a deteriorating process. However, the work of Fidler has long predicted that the metastatic cascade is a dynamic process, where disseminated tumor cells are constantly influenced by their surrounding microenvironment {1}. In conventional metastasis models, the selection of genetic and epigenetic alterations occurs mainly within the primary tumor, such that the late-disseminating cells are genetically similar to the primary tumor. In contrast, the data of Podsypanina and co-workers argue that early-disseminated tumor cells accumulate genetic alterations at these distant sites and that the resulting metastases are genetically distinct from their corresponding primary tumors. They elegantly demonstrate that normal mouse mammary epithelial cells survive at ectopic sites following injection into the bloodstream of Rag1-null mice. These mouse mammary epithelial cells survive until expression of the oncogenes they harbor (tetracycline-regulated forms of MYC and oncogenic Kras) is activated, thereby driving cell proliferation and colonization of a new lung metastasis site without ever having contributed to a primary tumor. In the absence of tetracycline activation, the cells, when isolated from the lung, could form mammary glands after re-implantation into mammary fat tissue, demonstrating the requirement for oncogenic activation at the distant site before a tumor formed. Perhaps even more intriguing is the number of mammary cells that survived in the lungs (~1.2 per 10,000 intravenously injected cells), compared with the relatively few metastases that arise from the injection of millions of tumor cells. Collectively, the findings suggest a note of caution about the use of conventional metastasis models. In particular, the use of advanced-stage cancer cell lines for metastasis research may be misleading. More importantly, the idea that therapeutic targets activated in primary tumors will also be activated in metastatic tumor cells may be untrue. A shift in our understanding of the molecular process driving cancer dissemination may provide novel insight into the prevention, diagnosis, and treatment of metastatic cancer. {1} Fidler, Nat Rev Cancer 2003, 3:453-458 [PMID: 12778135].Christos Sotiriou with Michail Ignatiadis
Jules Bordet Institute, Belgium
OncologyThis article adds to the growing evidence that tumor cell dissemination may be an early rather than a late event in metastatic progression. This study, together with others mentioned below, holds the promise to revisit the current model of metastatic progression and it may have significant implications on designing new trials for patients with early breast cancer.
Podsypanina et al. used a mouse model in order to provide evidence that activated oncogenes and cellular transformation are not required for 3 important steps of metastatic progression (i.e. survival in the circulation, extravasation and establishment of cells at ectopic sites). They show that these tasks can be accomplished even by untrasformed mammary cells. In the prevailing model of metastasis, the ability of tumor cells to metastasize is considered a late event in tumorigenesis. According to this model, cells that are able to metastasize are rare variants within the primary tumor that are able to perform efficiently the different steps of metastatic progression (i.e. intravasion of cells from primary tumors into blood vessels or lymphatics, survival in the circulation, extravasation, establishment at ectopic sites and malignant growth). However, recent studies have challenged this model. Indeed clinical studies on minimal residual disease {1,2} as well as on primary tumor gene expression profiling {3,4} have shown that the probability for developing metastasis may be predicted to some extent at the time of surgery even in small, node-negative breast cancers. Intriguingly, Husemann et al. have shown that epithelial tumor cells disseminate at the stage of hyperplasia in a murine model {5}. In the present article, Podsypanina et al. show, in a mouse model, that previously untransformed mouse mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. The investigators elegantly show that activated oncogenes and cellular transformation are not required for survival in the circulation, extravasation and establishment of cells at ectopic sites. References: {1} Braun et al., N Engl J Med 2005, 353:793-802 [PMID: 16120859]; {2} Ignatiadis et al., J Clin Oncol 2007, 25:5194-5202 [PMID: 17954712]; {3} van't Veer et al., Nature 2002, 415:530-536 [PMID: 11823860]; {4} Sotiriou et al., J Natl Cancer Inst 2006, 98:262-272 [PMID: 16478745]; {5} Husemann et al., Cancer Cell 2008, 13:58-68 [PMID: 18167340].
Science. 2008 Sep 26;321(5897):1841-4.
Seeding and propagation of untransformed mouse mammary cells in the lung.
Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H.
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. podsypak@mskcc.org
The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. We report that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes MYC and Kras(D12), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogene induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.
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