Understanding the molecular mechanisms driving metastasis

Massagué, Joan; Batlle, Eduard; Gomis, Roger R.

doi:10.1002/1878-0261.12024

Cited by 61 publications

(36 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have previously reported that metastatic lesions showed a completely different genetic profile and biological behavior compared to their primary lesion, including primary lesions created by inoculation in orthotopic versus ectopic sites (5, 6, 9, 16). This is in agreement with other studies that demonstrated the difference between primary and metastatic lesions (24–26). In addition, treatment response may be due to multiple factors, including microenvironment and cancer stem cells.…”

Section: Discussionsupporting

confidence: 94%

Murine breast cancer mastectomy model that predicts patient outcomes for drug development

Katsuta

Rashid

Takabe

2017

Journal of Surgical Research

View full text Add to dashboard Cite

Background Despite massive expenditures in preclinical studies, many breast cancer agents show efficacy in murine models but fail in human trials. In humans, metastatic disease determines survival, but preclinical murine models only evaluate drug efficacy against the primary tumor. We hypothesized that evaluating efficacy against metastatic breast cancer would more efficiently predict efficacy in a murine model than evaluating the primary tumor alone. This study (1) critically evaluated a murine tumor removal model with metastatic tumor burden quantification for breast cancer preclinical trials and (2) validated the model with an agent that previously passed preclinical trials but failed human trials. Materials and methods Tumorectomy and Halsted (radical) mastectomy procedures after inoculation of 4T1-luc2 cells were compared. The effect of AZD0530, an oral Src inhibitor that passed preclinical trials but failed human trials, was evaluated using an inoculation model with/without Halsted mastectomy. Results Significant amounts of residual disease were confirmed by bioluminescence (p = 0.003) and 100% developed local recurrence after tumorectomy versus 14% (p = 0.005) after Halsted mastectomy. Bioluminescence value at 15min after luciferin injection highly correlated with peak except for 24 hours after injection. AZD0530 significantly suppressed primary tumor burden compared with no treatment (p = 0.002); but not in lung metastases. In a Halsted mastectomy model, AZD0530 had no efficacy against lung metastases or difference in survival. Conclusions We critically evaluated and established a murine mastectomy model to evaluate metastatic tumors. It provides a new model for preclinical drug development that mimics the human adjuvant setting.

show abstract

Section: Discussionsupporting

confidence: 94%

Murine breast cancer mastectomy model that predicts patient outcomes for drug development

Katsuta

Rashid

Takabe

2017

Journal of Surgical Research

View full text Add to dashboard Cite

show abstract

“…Interestingly, some bone metastatic patients never progress to this point, while others rapidly progress to a skeletal-related event. While estrogen receptor (ER) status may account for some of these differences (ER+ patients typically have longer latency and therefore may not develop clinically detectable bone metastases [111]), it remains unclear how early the functional bone-remodeling unit is disrupted by this process. Can a few disseminated tumor cells significantly disrupt “coupling”?…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

Hallmarks of Bone Metastasis

Johnson

Suva

2017

Calcif Tissue Int

View full text Add to dashboard Cite

Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient’s quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

show abstract

“…It is suggested that more than 90% of deaths from cancer are not caused by the primary tumour but by the direct effects of metastatic deposits and from the metabolic burden of a rapidly growing tumour cell mass ( Jemal et al , 2011). Traditionally an orderly cascade of cellular behaviours was presumed to underlie the progression from a well circumscribed and localised tumour growth to distant spread, based on initial local invasion, entry into the vascular or lymphatic system, survival in those fluid channels followed by extravasation and colonisation in a distal site ( Massagué et al , 2017). However, this orderly progression is not borne out by current research and the mechanisms of metastatic spread remain controversial.…”

Section: Introductionmentioning

confidence: 99%

Embryonic zebrafish xenograft assay of human cancer metastasis

et al. 2018

View full text Add to dashboard Cite

Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish ( Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis.

show abstract

Understanding the molecular mechanisms driving metastasis

Cited by 61 publications

References 12 publications

Murine breast cancer mastectomy model that predicts patient outcomes for drug development

Murine breast cancer mastectomy model that predicts patient outcomes for drug development

Hallmarks of Bone Metastasis

Embryonic zebrafish xenograft assay of human cancer metastasis

Contact Info

Product

Resources

About