Biology, detection, and clinical implications of circulating tumor cells

Joosse, Simon A.; Gorges, Tobias M.; Pantel, Klaus

doi:10.15252/emmm.201303698

Cited by 449 publications

(488 citation statements)

References 112 publications

(146 reference statements)

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“…The numbers of cancer cells shed by tumours into the bloodstream may be exceedingly low, and the biological and clinical relevance of CTCs in sustaining malignant disease has been questioned 40 . However, as CTCs are shed by tumours on a stochastic rather than a deterministic basis 41 , they are expected to better recapitulate the distribution of different subclonal tumour populations (TABLE 1).…”

Section: Modelling Cancer Phenotypesmentioning

confidence: 99%

“…As mentioned above, a step forwards for minimally invasive tumour sampling is the isolation and characterization of CTCs, detected at low concentrations in the peripheral blood of patients with different solid tumours 40 . Although the role of CTCs in metastasis development is still uncertain 40 , their levels ostensibly correlate with patient survival and response to therapy [94][95][96] . These features mean that CTCs are promising tools to monitor cancer burden and drug susceptibility in metastatic and late-stage disease, when repetitive biopsies are not indicated.…”

Section: Modelling Metastatic Disease Subcutaneous Transplantation Umentioning

confidence: 99%

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Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

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Section: Modelling Cancer Phenotypesmentioning

confidence: 99%

Section: Modelling Metastatic Disease Subcutaneous Transplantation Umentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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“…However, determinations of serum CHI3L1 in cancer patients may be not tumor-specific due to secretion from inflamed normal tissues. High expression of CHI3L1 in solid tumors, as indicator of dissemination and poor prognosis, may at least partially be due to CHI3L1-positive CTCs (109).…”

Section: Chi3l1 In Inflammation and Cancermentioning

confidence: 99%

Circulating tumor cell interactions with macrophages: implications for biology and treatment

Hamilton¹,

Rath²

2017

Transl. Lung Cancer Res.

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CTCs. SCLC has an unfavorable prognosis due to rapid dissemination and early chemoresistant relapses. SCLC CTCs recruit macrophages and elicit secretion of various cytokines and the six CTC lines expresschitinase-3-like-1 (CHI3L1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) in abundance. CHI3L1 is cytokine/growth factor expressed in inflammation and cancer and found to be correlated to metastasis and a dismal prognosis. In conclusion, SCLC CTCs have acquired the essential means for aggressiveness and invasion in a tumor microenvironment specifically shaped by macrophages and inflammation.

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“…After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells.…”

mentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

164

133

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Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

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Biology, detection, and clinical implications of circulating tumor cells

Cited by 449 publications

References 112 publications

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Circulating tumor cell interactions with macrophages: implications for biology and treatment

The Multiple Roles of Exosomes in Metastasis

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