The number of available breast cancer cell (BCC) lines is small, and only a very few of them have been extensively studied. Whether they are representative of the tumours from which they originated remains a matter of debate. Whether their diversity mirrors the well-known inter-tumoural heterogeneity is another essential question. While numerous similarities have long been found between cell lines and tumours, recent technical advances, including the use of micro-arrays and comparative genetic analysis, have brought new data to the discussion. This paper presents most of the BCC lines that have been described in some detail to date. It evaluates the accuracy of the few of them widely used (MCF-7, T-47D, BT-474, SK-BR-3, MDA-MB-231, Hs578T) as tumour models. It is concluded that BCC lines are likely to reflect, to a large extent, the features of cancer cells in vivo. The importance of oestrogen receptor-alpha (gene ESR1) and Her-2/neu (ERBB2) as classifiers for cell lines and tumours is underlined. The recourse to a larger set of cell lines is suggested since the exact origin of some of the widely used lines remains ambiguous. Investigations on additional specific lines are expected to improve our knowledge of BCC and of the dialogue that these maintain with their surrounding normal cells in vivo.

Relevance of breast cancer cell lines as models for breast tumours: an update

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

https://clincancerres.aacrjournals.org/content/clincanres/12/15/4652.full.pdf

An In vivo Platform for Translational Drug Development in Pancreatic Cancer

Purpose: To establish a panel of human breast cancer (HBC) xenografts in immunodeficient mice suitable for pharmacologic preclinical assays. Experimental Design: 200 samples of HBCs were grafted into Swiss nude mice. Twenty-five transplantable xenografts were established (12.5%). Their characterization included histology, p53 status, genetic analysis by array comparative genomic hybridization, gene expression by Western blotting, and quantitative reverse transcription-PCR. Biological profiles of nine xenografts were compared with those of the corresponding patient9s tumor. Chemosensitivities of 17 xenografts to a combination of Adriamycin and cyclophosphamide (AC), docetaxel, trastuzumab, and Degarelix were evaluated. Results: Almost all patient tumors established as xenografts displayed an aggressive phenotype, i.e., high-grade, triple-negative status. The histology of the xenografts recapitulated the features of the original tumors. Mutation of p53 and inactivation of Rb and PTEN proteins were found in 83%, 30%, and 42% of HBC xenografts, respectively. Two HBCx had an ERBB2 (HER2) amplification. Large variations were observed in the expression of HER family receptors and in genomic profiles. Genomic alterations were close to those of original samples in paired tumors. Three xenografts formed lung metastases. A total of 15 of the 17 HBCx (88%) responded to AC, and 8 (47%) responded to docetaxel. One ERBB2-amplified xenograft responded to trastuzumab, whereas the other did not. The drug response of HBC xenografts was concordant with that of the patient9s tumor in five of seven analyzable cases. Conclusions: This panel of breast cancer xenografts includes 15 triple-negative, one ER positive and 2 ERBB2 positive. This panel represents a useful preclinical tool for testing new agents and protocols and for further exploration of the biological basis of drug responses.

https://clincancerres.aacrjournals.org/content/clincanres/13/13/3989.full.pdf

A New Model of Patient Tumor-Derived Breast Cancer Xenografts for Preclinical Assays

At the time of diagnosis, tumors are already complex mixtures of cells despite having arisen from single cells. One of the earliest detectable changes in transformed cells is a greater genetic instability than their normal counterparts [1–8]. Even before they become tumorigenic, transformed cells (anchorageindependent, not contact-inhibited, and immortal) display genomic instability that is apparently the driving force for further progression. Genetic instability is particularly important for generation of heterogeneity within tumors [2,4,9–11]. A heterogenous population is then subjected to selective pressures that cause evolution toward increasingly malignant characteristics (i.e. invasion and metastasis). In addition to these types of intrinsic cellular changes, tumor cells exist in a complex milieu, exchanging signals with other tumor cell subpopulations and host cells. Heppner likens this to ‘tumor cell societies’ [12]. The sum of signals received by tumor cells, coupled with intrinsic properties, determines their individual behaviors as well as the overall tumor’s behavior. Metastasis is the ultimate step in the multistage process of tumor progression [13–21]. Subsets of neoplastic cells are able to form distinct tumor colonies from the primary tumor. Development of metastasis requires tumor cells to complete a complex cascade of events. First, malignant cells invade adjacent tissues and penetrate into the lymphatic and/or circulatory systems. Cells then detach from the primary tumor mass and disseminate. During transport, tumor cells can travel individually or as emboli composed of tumor cells (homotypic) or tumor cells and host cells (heterotypic). At the secondary site, tumor cells or emboli either arrest due to physical limitations (e.g. too large to traverse a capillary lumen) or bind to specific molecules in particular organs or tissues. Once there, tumor cells must then proliferate either in the vasculature or extravasate into surrounding tissue [22,23]. To form macroscopic metastases, cells must then recruit a vascular supply [19,24–31]. Fewer than 0.1% of cells that enter the vasculature survive to form clinically detectable macroscopic metastases [32]. At which step(s) of the metastatic cascade circulating tumor cells commonly succumb is debatable [22,23,33,34]. The greatest complication to successful cure of cancer is metastasis. During the past half-century, the proportion of patients surviving long-term has increased significantly [35]; however, patients diagnosed with metastatic disease invariably have poor prognoses. A majority die within 5 years. In contrast, when tumors are detected before they have spread, cure rates approach 100%. Unfortunately, 60–70% of patients have occult metastatic disease at the time of diagnosis [36]. Development of recurrence (whether local or distant) is also a bad sign. These statistics highlight how important it is to understand metastasis if treatment of patients with advanced disease is to improve.

Technical considerations for studying cancer metastasis in vivo.

Gene amplification and tumor progression

Four hundred and thirty-three human breast carcinomas and 23 cell lines derived from human breast carcinomas were heterotransplanted in nude mice. Twenty-eight tumors and 13 cell lines took and could be serially transplanted. Their human origin was established by isozyme analysis performed on successive passages. Sixteen primary infiltrating duct-cell carcinomas (PIDC) took, from a total of 262 transplanted (6.1%). This is in striking contrast to the greater than 50% rate of takes of most major cancers of epithelial origin. All 16 PIDC growing in nude mice were highly cellular and lacked desmoplastic hyperplasia. The clinical prognosis of the PIDC patients whose tumors were successfully transplanted was poor. Ten of 16 (63%) died of their disease within 3 years, compared to only 49 (20%) of the 246 PIDC patients whose tumors did not take in nude mice. This could not be attributed to later stage disease of the tumors that took, because only 15% of these patients had 4 or more positive axillary lymph nodes as opposed to 28% of the patients whose tumors did not take. Sixty-four percent of the breast carcinomas growing in nude mice exhibited amplification of the HER-2/neu oncogene which is also correlated with poor prognosis in human breast cancer. It is possible that the nude mouse is more susceptible to a population of highly invasive and lethal breast carcinomas.

Heterotransplantation of human breast carcinomas in nude mice. Correlation between successful heterotransplants, poor prognosis and amplification of the HER-2/neu oncogene.

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Heterotransplantation of human breast carcinomas in nude mice. Correlation between successful heterotransplants, poor prognosis and amplification of the HER-2/neu oncogene.