Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohorts
2.2. Sample Collection
2.3. CTC Isolation
2.4. CTC Characterization
2.5. Detection of Circulating Biomarkers
2.6. Statistical Analysis
3. Results
3.1. Study Design and Patient Data
3.2. Assessment of Different Serum and Blood Biomarkers
3.3. The OS Value of CTC Count Versus PSA Level
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
- Bell, K.J.; Del Mar, C.; Wright, G.; Dickinson, J.; Glasziou, P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int. J. Cancer 2015, 137, 1749–1757. [Google Scholar] [CrossRef] [PubMed]
- Jemal, A.; Culp, M.B.; Ma, J.; Islami, F.; Fedewa, S. Prostate Cancer Incidence 5 Years After US Preventive Services Task Force Recommendations Against Screening. J. Natl. Cancer Inst. 2021, 113, 64–71. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [Green Version]
- Gandaglia, G.; Abdollah, F.; Schiffmann, J.; Trudeau, V.; Shariat, S.F.; Kim, S.P.; Perrotte, P.; Montorsi, F.; Briganti, A.; Trinh, Q.-D.; et al. Distribution of metastatic sites in patients with prostate cancer: A population-based analysis. Prostate 2014, 74, 210–216. [Google Scholar] [CrossRef]
- Welch, D.R.; Hurst, D.R. Defining the Hallmarks of Metastasis. Cancer Res. 2019, 79, 3011–3027. [Google Scholar] [CrossRef]
- Carceles-Cordon, M.; Kelly, W.K.; Gomella, L.; Knudsen, K.E.; Rodriguez-Bravo, V.; Domingo-Domenech, J. Cellular rewiring in lethal prostate cancer: The architect of drug resistance. Nat. Rev. Urol. 2020, 17, 292–307. [Google Scholar] [CrossRef] [PubMed]
- Nuhn, P.; De Bono, J.S.; Fizazi, K.; Freedland, S.J.; Grilli, M.; Kantoff, P.W.; Sonpavde, G.; Sternberg, C.N.; Yegnasubramanian, S.; Antonarakis, E.S. Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology. Eur. Urol. 2019, 75, 88–99. [Google Scholar] [CrossRef]
- Lorente, D.; Ravi, P.; Mehra, N.; Pezaro, C.; Omlin, A.; Gilman, A.; Miranda, M.; Rescigno, P.; Kolinsky, M.; Porta, N.; et al. Interrogating Metastatic Prostate Cancer Treatment Switch Decisions: A Multi-institutional Survey. Eur. Urol. Focus 2018, 4, 235–244. [Google Scholar] [CrossRef] [Green Version]
- Caffo, O.; Maines, F.; Kinspergher, S.; Veccia, A.; Messina, C. Sequencing strategies in the new treatment landscape of prostate cancer. Futur. Oncol. 2019, 15, 2967–2982. [Google Scholar] [CrossRef]
- Mottet, N.; van den Bergh, R.C.; Briers, E.; Van den Broeck, T.; Cumberbatch, M.G.; De Santis, M.; Cornford, P. EAU—EANM—ESTRO—ESUR—SIOG Guidelines on Prostate Cancer; European Association of Urology: Arnhem, The Netherlands, 2019. [Google Scholar]
- Massague, J.; Obenauf, A.C. Metastatic colonization by circulating tumour cells. Nature 2016, 529, 298–306. [Google Scholar] [CrossRef]
- Lambert, A.W.; Pattabiraman, D.R.; Weinberg, R.A. Emerging Biological Principles of Metastasis. Cell 2017, 168, 670–691. [Google Scholar] [CrossRef] [Green Version]
- Lozar, T.; Gersak, K.; Cemazar, M.; Kuhar, C.G.; Jesenko, T. The biology and clinical potential of circulating tumor cells. Radiol. Oncol. 2019, 53, 131–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Araki, S.; Omori, Y.; Lyn, D.; Singh, R.K.; Meinbach, D.M.; Sandman, Y.; Lokeshwar, V.B.; Lokeshwar, B.L. Interleukin-8 Is a Molecular Determinant of Androgen Independence and Progression in Prostate Cancer. Cancer Res. 2007, 67, 6854–6862. [Google Scholar] [CrossRef] [Green Version]
- Waugh, D.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 2008, 14, 6735–6741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aguilar-Saavedra, J.A.; Anjos, N.; Cantrill, R.; Carvalho, J.; Castro, N.F.; Conde Muiño, P. Search for magnetic monopoles in sqrt[s]=7 TeV pp collisions with the ATLAS detector. Phys. Rev. Lett. 2012, 109, 261803. [Google Scholar]
- Nguyen, D.P.; Li, J.; Tewari, A.K. Inflammation and prostate cancer: The role of interleukin 6 (IL-6). BJU Int. 2014, 113, 986–992. [Google Scholar] [CrossRef] [PubMed]
- Ueda, T.; Bruchovsky, N.; Sadar, M. Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways. J. Biol. Chem. 2002, 277, 7076–7085. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Culig, Z. Interleukin-6 Function and Targeting in Prostate Cancer. Adv. Exp. Med. Biol. 2021, 1290, 1–8. [Google Scholar] [CrossRef]
- Qiu, Y.; Ravi, L.; Kung, H.-J. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nat. Cell Biol. 1998, 393, 83–85. [Google Scholar] [CrossRef]
- Perrier, A.; Gligorov, J.; Lefevre, G.; Boissan, M. The extracellular domain of Her2 in serum as a biomarker of breast cancer. Lab. Investig. 2018, 98, 696–707. [Google Scholar] [CrossRef]
- Craft, N.; Shostak, Y.; Carey, M.; Sawyers, C.L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat. Med. 1999, 5, 280–285. [Google Scholar] [CrossRef]
- Miller, D.R.; Ingersoll, M.A.; Lin, M.-F. ErbB-2 signaling in advanced prostate cancer progression and potential therapy. Endocrine-Relat. Cancer 2019, 26, R195–R209. [Google Scholar] [CrossRef]
- Ma, J.-W.; Wang, X.; Chang, L.; Zhong, X.-Y.; Jing, H.; Zhu, X.; Wang, S.; Xiao, W. CD44 collaborates with ERBB2 mediate radiation resistance via p38 phosphorylation and DNA homologous recombination pathway in prostate cancer. Exp. Cell Res. 2018, 370, 58–67. [Google Scholar] [CrossRef]
- Hiraga, T.; Ito, S.; Nakamura, H. Cancer Stem-like Cell Marker CD44 Promotes Bone Metastases by Enhancing Tumorigenicity, Cell Motility, and Hyaluronan Production. Cancer Res. 2013, 73, 4112–4122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Senbanjo, L.T.; AlJohani, H.; Majumdar, S.; Chellaiah, M.A. Characterization of CD44 intracellular domain interaction with RUNX2 in PC3 human prostate cancer cells. Cell Commun. Signal. 2019, 17, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baron, R.; Rawadi, G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 2007, 148, 2635–2643. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pakula, H.; Xiang, D.; Li, Z. A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland. Cancers 2017, 9, 14. [Google Scholar] [CrossRef] [PubMed]
- Theil, G.; Boehm, C.; Fischer, K.; Bialek, J.; Hoda, R.; Weber, E.; Schönburg, S.; Kawan, F.; Fornara, P. In vivo isolation of circulating tumor cells in patients with different stages of prostate cancer. Oncol. Lett. 2021, 21, 1–8. [Google Scholar] [CrossRef]
- Kuske, A.; Gorges, T.M.; Tennstedt, P.; Tiebel, A.-K.; Pompe, R.S.; Preißer, F.; Prues, S.; Mazel, M.; Markou, A.; Lianidou, E.; et al. Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients. Sci. Rep. 2016, 6, 39736. [Google Scholar] [CrossRef] [Green Version]
- De Bono, J.S.; Scher, H.I.; Montgomery, R.B.; Parker, C.; Miller, M.C.; Tissing, H.; Doyle, G.V.; Terstappen, L.; Pienta, K.; Raghavan, D. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin. Cancer Res. 2008, 14, 6302–6309. [Google Scholar] [CrossRef] [Green Version]
- Allard, W.J.; Matera, J.; Miller, M.C.; Repollet, M.; Connelly, M.C.; Rao, C.; Tibbe, A.G.J.; Uhr, J.W.; Terstappen, L.W.M.M. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 2004, 10, 6897–6904. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Llopis, P.M.; Senft, R.A.; Ross-Elliott, T.J.; Stephansky, R.; Keeley, D.P.; Koshar, P.; Marqués, G.; Gao, Y.-S.; Carlson, B.R.; Pengo, T.; et al. Best practices and tools for reporting reproducible fluorescence microscopy methods. Nat. Methods 2021, 1–14. [Google Scholar] [CrossRef]
- Theil, G.; Fornara, P.; Bialek, J. Position of Circulating Tumor Cells in the Clinical Routine in Prostate Cancer and Breast Cancer Patients. Cancers 2020, 12, 3782. [Google Scholar] [CrossRef]
- Alix-Panabières, C.; Pantel, K. Technologies for detection of circulating tumor cells: Facts and vision. Lab Chip 2013, 14, 57–62. [Google Scholar] [CrossRef] [PubMed]
- Saucedo-Zeni, N.; Mewes, S.; Niestroj, R.; Gasiorowski, L.; Murawa, D.; Nowaczyk, P.; Lücke, K. A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int. J. Oncol. 2012, 41, 1241–1250. [Google Scholar]
- Chen, S.; Tauber, G.; Langsenlehner, T.; Schmölzer, L.M.; Pötscher, M.; Riethdorf, S.; Kuske, A.; Leitinger, G.; Kashofer, K.; Czyż, Z.T.; et al. In Vivo Detection of Circulating Tumor Cells in High-Risk Non-Metastatic Prostate Cancer Patients Undergoing Radiotherapy. Cancers 2019, 11, 933. [Google Scholar] [CrossRef] [Green Version]
- Buonerba, C.; Ferro, M.; Dolce, P.; Crocetto, F.; Verde, A.; Lucarelli, G.; Scafuri, L.; Facchini, S.; Vaia, A.; Marinelli, A.; et al. Predictors of efficacy of androgen-receptor-axis-targeted therapies in patients with metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis. Crit. Rev. Oncol. 2020, 151, 102992. [Google Scholar] [CrossRef]
- Ferro, M.; Lucarelli, G.; Crocetto, F.; Dolce, P.; Verde, A.; La Civita, E.; Zappavigna, S.; de Cobelli, O.; Di Lorenzo, G.; Facchini, B.A.; et al. First-line systemic therapy for metastatic castration-sensitive prostate cancer: An updated systematic review with novel findings. Crit. Rev. Oncol. 2021, 157, 103198. [Google Scholar] [CrossRef]
- Cieślikowski, W.A.; Budna-Tukan, J.; Świerczewska, M.; Ida, A.; Hrab, M.; Jankowiak, A.; Mazel, M.; Nowicki, M.; Milecki, P.; Pantel, K.; et al. Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer. Cancers 2020, 12, 160. [Google Scholar] [CrossRef] [Green Version]
- Lorente, D.; Olmos, D.; Mateo, J.; Dolling, D.; Bianchini, D.; Seed, G.; Flohr, P.; Crespo, M.; Figueiredo, I.; Miranda, S.; et al. Circulating tumour cell increase as a biomarker of disease progression in metastatic castration-resistant prostate cancer patients with low baseline CTC counts. Ann. Oncol. 2018, 29, 1554–1560. [Google Scholar] [CrossRef] [PubMed]
- Scher, H.I.; Lu, D.; Schreiber, N.A.; Louw, J.; Graf, R.P.; Vargas, H.A.; Johnson, A.; Jendrisak, A.; Bambury, R.; Danila, D.; et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker with Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol. 2016, 2, 1441–1449. [Google Scholar] [CrossRef] [PubMed]
- Scher, H.I.; Heller, G.; Molina, A.; Attard, G.; Danila, D.C.; Jia, X.; de Bono, J.S. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 2015, 33, 1348–1355. [Google Scholar] [CrossRef]
- Aufderklamm, S.; Hennenlotter, J.; Leidenberger, P.; Rausch, S.; Hohneder, A.; Kühs, U.; Todenhöfer, T. Systemic Alterations of Wnt Inhibitors in Patients with Prostate Cancer and Bone Metastases. Dis. Markers 2018, 2018, 1874598. [Google Scholar] [CrossRef]
- Thiele, S.; Rauner, M.; Goettsch, C.; Rachner, T.D.; Benad, P.; Fuessel, S.; Erdmann, K.; Hamann, C.; Baretton, G.B.; Wirth, M.P.; et al. Expression profile of WNT molecules in prostate cancer and its regulation by aminobisphosphonates. J. Cell. Biochem. 2011, 112, 1593–1600. [Google Scholar] [CrossRef]
- Yeremenko, N.; Zwerina, K.; Rigter, G.; Pots, D.; Fonseca, J.E.; Zwerina, J.; Schett, G.; Baeten, D. Brief Report: Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint. Arthritis Rheumatol. 2015, 67, 2071–2075. [Google Scholar] [CrossRef] [PubMed]
- Culig, Z. Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. Am. J. Clin. Exp. Urol. 2014, 2, 231–238. [Google Scholar] [PubMed]
- Nakashima, J.; Tachibana, M.; Horiguchi, Y.; Oya, M.; Ohigashi, T.; Asakura, H.; Murai, M. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin. Cancer Res. 2000, 6, 2702–2706. [Google Scholar] [PubMed]
- Maynard, J.P.; Ertunc, O.; Kulac, I.; Del Valle, J.A.B.; De Marzo, A.M.; Sfanos, K.S. IL8 Expression Is Associated with Prostate Cancer Aggressiveness and Androgen Receptor Loss in Primary and Metastatic Prostate Cancer. Mol. Cancer Res. 2019, 18, 153–165. [Google Scholar] [CrossRef] [Green Version]
- Roumeguere, T.; Legrand, F.; El Rassy, E.; Kaitouni, M.I.; Albisinni, S.; Rousseau, A.; Vanhaeverbeek, M.; Rorive, S.; Decaestecker, C.; Debeir, O.; et al. A prospective clinical study of the implications of IL-8 in the diagnosis, aggressiveness and prognosis of prostate cancer. Futur. Sci. OA 2018, 4, FSO266. [Google Scholar] [CrossRef]
- Armstrong, A.J. Epithelial-mesenchymal transition in cancer progression. Clin. Adv. Hematol. Oncol. 2011, 9, 941–943. [Google Scholar]
- Yang, Y.-J.; Kong, Y.-Y.; Li, G.-X.; Wang, Y.; Ye, D.-W.; Dai, B. Phenotypes of circulating tumour cells predict time to castration resistance in metastatic castration-sensitive prostate cancer. BJU Int. 2019, 124, 258–267. [Google Scholar] [CrossRef] [PubMed]
- Josefsson, A.; Larsson, K.; Månsson, M.; Bjorkman, J.; Rohlová, E.; Åhs, D.; Brisby, H.; Damber, J.-E.; Welén, K. Circulating tumor cells mirror bone metastatic phenotype in prostate cancer. Oncotarget 2018, 9, 29403–29413. [Google Scholar] [CrossRef]
- Ahmad, I.; Gao, M.; Patel, R.; Leung, H.Y. Modelling synergistic interactions between HER2, Sprouty2 and PTEN in driving prostate carcinogenesis. Asian J. Androl. 2013, 15, 323–327. [Google Scholar] [CrossRef] [PubMed]
- Antonarakis, E.S.; Lu, C.; Wang, H.; Luber, B.; Nakazawa, M.; Roeser, J.C.; Chen, Y.; Mohammad, T.A.; Chen, Y.; Fedor, H.L.; et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. N. Engl. J. Med. 2014, 371, 1028–1038. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Di Lorenzo, G.; Zappavigna, S.; Crocetto, F.; Giuliano, M.; Ribera, D.; Morra, R.; Buonerba, C. Assessment of Total, PTEN(-), and AR-V7(+) Circulating Tumor Cell Count by Flow Cytometry in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide. Clin. Genitourin. Cancer 2021, in press. [Google Scholar]
Characteristics | mCRPC | PCa-l |
---|---|---|
Patient (n) | 12 | 16 |
Median (range), years | 69 (53–72) | 63 (56–75) |
Median (range) BMI | 27.5 (20.8–39) | 29.7 (22.5–34.5) |
Median PSA (range), ng/mL at baseline | 25.6 (35–1200) | 8.2 (0.64–38.8) |
Median PSA (range), ng/mL at the last visit | 44.95 (0.04–903) | 0,04 (0.04–0.06) |
Median CRP (range), mg/mL | 7.3 (1.8–94.8) | 2.3 (1–26.2) |
at baseline | ||
Median HB (range), nmol/L | 7 (6.3–9.5) | 9.4 (7.9–10.5) |
at baseline | ||
Gleason sum, n (%) | ||
≤7 | 2 (16.67) | 11 (64.7) |
>7 | 10 (83.33) | 6 (35.3) |
Sites of metastasis, n (%) | ||
Bone | 12 (100) | |
Visceral | 4 (33.3) | |
Nodal | 10 (83.3) | |
Prior treatments, n (%) | ||
TURP | 5 (41.7) | |
Androgen treatment | 12 (100) | |
Radiation | 9 (75) | |
Treatments between baseline and study end, n (%) | ||
TURP | ||
Surgery (RP) | 14 (82.3) | |
HIFU | 2 (11.8) | |
Radiation | 10 (83.3) | |
Bone-targeted therapy | 12 (100) | |
Chemotherapy | ||
Docetaxel | 10 (83.3) | |
Cabazitaxel | 3 * (25) |
Median (Range) | mCRPC V1–V6 | PCa-l | V1 | p-Value |
---|---|---|---|---|
V2 + V3 | ||||
CD44 (pg/mL) | 710 (205.9–4878) | 777.1 (230.6–3382) | 783.6 (386–2440) | 0.70 |
DKK-1 (pg/mL) | 4625 (566.9–8878) | 3939 (1632–10937) | 3976 (1273–7988) | 0.80 |
sHer2 (ng/mL) | 3.3 (0.83–16.46) | 3.3 (1.1–7.7) | 3.5 (1.27–8.4) | 0.39 |
IL-6 (pg/mL) | 11.7 (1.91–180) | 5.6 (1.5–587.2) | 8.2 (1.0–589) | 0.24 |
IL-8 (pg/mL) | 20 (1.98–112.7) | 10.8 (4.8–1127) | 13.2 (2.6–1216) | 0.27 |
CTC_CC | 4 (0–820) | 0 (0–5) | 0 (0–9) | <0.0001 |
CTC_CS | 8.5 (0–1428) | 0 (0–1) | 0 | <0.0001 |
PSA (ng/mL) | 18.5 (1–1120) | 8.2 (0.64–38.8) | 0.04 (0.04–1.12) | <0.0001 |
CRP (ng/mL) | 7.3 (1.8–94.8) | 2.1 (1–26.4) | n.d. | 0.03 |
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Theil, G.; Lindner, C.; Bialek, J.; Fornara, P. Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer. Life 2021, 11, 664. https://doi.org/10.3390/life11070664
Theil G, Lindner C, Bialek J, Fornara P. Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer. Life. 2021; 11(7):664. https://doi.org/10.3390/life11070664
Chicago/Turabian StyleTheil, Gerit, Carlotta Lindner, Joanna Bialek, and Paolo Fornara. 2021. "Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer" Life 11, no. 7: 664. https://doi.org/10.3390/life11070664