Fibroblasts Contribute to Melanoma Tumor Growth and Drug Resistance

Flach, E. H.; Rebecca, Vito W.; Herlyn, Meenhard; Smalley, Keiran S.M.; Anderson, Alexander R.A.

doi:10.1021/mp200421k

Cited by 119 publications

(109 citation statements)

References 33 publications

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“…We have chosen human melanoma as a model system because the interaction between tumor cells and carcinoma-associated fibroblasts seems to be crucial for tumor growth and the development of drugs resistance (33). As shown by Flach and colleagues, melanoma cells stimulate the recruitment of fibroblasts and activate them by a so far unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…As shown by Flach and colleagues, melanoma cells stimulate the recruitment of fibroblasts and activate them by a so far unknown mechanism. In turn, these activated fibroblasts contribute to melanoma progression by providing both structural and chemical support (33). Incomplete abolishment of tumor cells by a short duration of kinase inhibitor therapy led to a transient reduction of tumor cells that was counteracted by an accelerated regrowth of tumor cells supported by the large fibroblast population that remained posttreatment.…”

Section: Discussionmentioning

confidence: 99%

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Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

Fischer

Chaitanya

Wüest

et al. 2012

Clinical Cancer Research

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Purpose: Fibroblast activation protein (FAP) is a serine protease that has emerged as a promising target for cancer therapy, either by direct abrogation of its proinvasive activity or by specific targeting of FAP-expressing cells with cytotoxic immunoconjugates. We aimed to select novel human-mouse crossreactive antibodies and to test suitability for tumor therapy as radioimmunoconjugates in a preclinical model.Experimental Design: Human Fab fragments that bind to human and murine FAP were selected from an antibody phage library. Two candidates (ESC11 and ESC14) were engineered into fully human IgG1 antibodies and further characterized. We investigated the intracellular trafficking of ESC11 and ESC14 in live cells by confocal microscopy and analyzed the biodistribution and therapeutic effects of anti-FAP antibodies labeled with the b-emitting radionuclide 177 Lu in a melanoma xenograft nude mouse model. Results were compared with vF19, a humanized variant of an anti-FAP antibody that has been previously used in clinical trials.Results: The two antibodies bound selectively to both human and mouse FAP, with affinities in the low nanomolar range. Binding to FAP-expressing melanoma cells resulted in rapid internalization of FAPantibody complexes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

Fischer

Chaitanya

Wüest

et al. 2012

Clinical Cancer Research

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“…3D spheroids may be used as simple cancer cell line spheroids, co-cultures of cancer cells with other cell types (e.g. fibroblasts) within the spheroid (35) or as a culture for the maintenance of patient tissues (36).…”

Section: D Spheroid Modelsmentioning

confidence: 99%

Modeling nasopharyngeal carcinoma in three dimensions

et al. 2017

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Abstract. Nasopharyngeal carcinoma (NPC) is a type of cancer endemic in Asia, including Malaysia, Southern China, Hong Kong and Taiwan. Treatment resistance, particularly in recurring cases, remains a challenge. Thus, studies to develop novel therapeutic agents are important. Potential therapeutic compounds may be effectively examined using two-dimensional (2D) cell culture models, three-dimensional (3D) spheroid models or in vivo animal models. The majority of drug assessments for cancers, including for NPC, are currently performed with 2D cell culture models. This model offers economical and high-throughput screening advantages. However, 2D cell culture models cannot recapitulate the architecture and the microenvironment of a tumor. In vivo models may recapitulate certain architectural and microenvironmental conditions of a tumor, however, these are not feasible for the screening of large numbers of compounds. By contrast, 3D spheroid models may be able to recapitulate a physiological microenvironment not observed in 2D cell culture models, in addition to avoiding the impediments of in vivo animal models. Thus, the 3D spheroid model offers a more representative model for the study of NPC growth, invasion and drug response, which may be cost-effective without forgoing quality. Contents1. Introduction 2. 2D cell culture models 3. In vivo animal models 4. 3D spheroid models 5. 3D spheroid models for high-throughput drug screening 6. NPC 3D spheroids 7. Conclusion IntroductionNasopharyngeal carcinoma (NPC) is a type of cancer that affects the nasopharynx, commonly at the posterior and superior region in the fossa of Rosenmüller (1). It is a geographically distinct cancer, which is prevalent in south-east Asia, southern China and southern Africa (2). Viral, dietary, hereditary and lifestyle factors have been identified as risk factors for NPC (2). Current NPC treatment consists of radiotherapy, chemotherapy or chemo-radiotherapy; treatment resistance, particularly in advanced and recurrent cases of NPC, remains a challenge (2). NPC is staged according to the TNM system, whereby T describes the primary tumor invasion to the tissue or organs near the nasopharynx, N describes the spread to the lymph nodes and M indicates the metastasis of the tumor. NPC is usually detected at a late stage (III or IV) (2). Early-stage NPC has unspecific and ambiguous clinical symptoms such as neck lumps, bloodstained sputum, mild hearing loss and a unilateral headache which may be ignored by its sufferer or misdiagnosed by a doctor (3). Ultimately, this leads to a late disease presentation as well as detection. The pathogenesis of NPC involves genetic and epigenetic changes in the nasopharyngeal epithelium (4). Previous studies have improved current understanding of the potential molecular targets and signaling pathways involved in NPC pathogenesis, which has assisted the development of targeted therapies for the treatment of NPC, including cetuximab (Erbitux

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“…In a 3D co-culture model Flach and colleagues (2011) found that melanoma spheroids could recruit and incorporate fibroblasts. The presence of the melanoma cell soluble factors that recruited the fibroblasts also increased the rate of wound closure as much as 38%, indicating an increase in the secretion of fibroblast associated factors 171 .…”

Section: Melanoma and The Tumor Microenvironmentmentioning

confidence: 95%

“…Myofibroblasts are larger and more spindle-like in composition than regular fibroblasts; they also typically divide faster and produce more ECM 159,[169][170][171] .…”

Section: Melanoma and The Tumor Microenvironmentmentioning

confidence: 99%

The Role of Endothelin 3 in Melanoma Progression and Metastasis

Chin¹

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Fibroblasts Contribute to Melanoma Tumor Growth and Drug Resistance

Cited by 119 publications

References 33 publications

Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

Modeling nasopharyngeal carcinoma in three dimensions

The Role of Endothelin 3 in Melanoma Progression and Metastasis

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