Cancer Research and Treatment

Review Article

Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy: Chang W Song, Hyunkyung Kim, Mi-Sook Kim, Heon J Park, Sun-Ha Paek, Stephanie Terezakis, L Chinsoo Cho; Received March 12, 2024 Accepted June 4, 2024 Published online June 5, 2024; DOI: https://doi.org/10.4143/crt.2024.255 [Epub ahead of print]

Abstract PDF PubReader ePub: Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

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Original Articles

Lung and Thoracic cancer

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma: Hyun Jung Kwon, Sejoon Lee, Yeon Bi Han, Jeonghyo Lee, Soohyeon Kwon, Hyojin Kim, Jin-Haeng Chung; Cancer Res Treat. 2024;56(2):442-454. Published online November 14, 2023; DOI: https://doi.org/10.4143/crt.2023.764

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non–small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples.
Materials and Methods
A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed.
Results
TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs.
Conclusion
Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

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PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid Carcinoma
Shipra Agarwal, Chan Kwon Jung, Pranitha Gaddam, Mitsuyoshi Hirokawa, Takuya Higashiyama, Jen-Fan Hang, Wei-An Lai, Somboon Keelawat, Zhiyan Liu, Hee Young Na, So Yeon Park, Junya Fukuoka, Shinya Satoh, Zhanna Mussazhanova, Masahiro Nakashima, Kennichi Ka
American Journal of Surgical Pathology.2024; 48(10): 1233. CrossRef

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Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer: Hyun-Seock Shin, Juwhan Choi, Jinhwan Lee, Sung Yong Lee; Cancer Res Treat. 2022;54(2):458-468. Published online September 10, 2021; DOI: https://doi.org/10.4143/crt.2021.425

Abstract PDF Supplementary Material PubReader ePub

Purpose
Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.
Materials and Methods
The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.
Results
The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.
Conclusion
HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.

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Zhijie Wang, Lin Yuan, Xiaotong Liao, Xia Guo, Jianjun Chen
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Xiaoran Ma, Jibiao Wu, Bin Wang, Cun Liu, Lijuan Liu, Changgang Sun
International Journal of Oncology.2022;[Epub] CrossRef

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PD-L1 Testing in Gastric Cancer by the Combined Positive Score of the 22C3 PharmDx and SP263 Assay with Clinically Relevant Cut-offs: Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Keun-Wook Lee, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee; Cancer Res Treat. 2020;52(3):661-670. Published online January 10, 2020; DOI: https://doi.org/10.4143/crt.2019.718

Abstract PDF Supplementary Material PubReader ePub

Purpose
We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients.
Materials and Methods
The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists.
Results
The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability.
Conclusion
Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

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Retrospective Molecular Epidemiology Study of PD-L1 Expression in Patients with EGFR-Mutant Non-small Cell Lung Cancer: Jong Ho Cho, Wei Zhou, Yoon-La Choi, Jong-Mu Sun, Hyejoo Choi, Tae-Eun Kim, Marisa Dolled-Filhart, Kenneth Emancipator, Mary Anne Rutkowski, Jhingook Kim; Cancer Res Treat. 2018;50(1):95-102. Published online March 17, 2017; DOI: https://doi.org/10.4143/crt.2016.591

Abstract PDF PubReader ePub

Purpose
Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
Materials and Methods
We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR-mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis.
Results
All patients had ≥ 1 EGFR mutation—54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1–positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1–positive groups (TPS ≥ 1%) compared with the PD-L1–negative group (median, 35 months).
Conclusion
PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR-mutant NSCLC.

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Yi Dong, Liaqat Khan, Yi Yao
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Activatable near-infrared fluorescence probe for real-time imaging of PD-L1 expression in tumors
Hyunjin Kim, Maixian Liu, Chan Hyeok Park, Byung Il Lee, Hyonchol Jang, Yongdoo Choi
Journal of Materials Chemistry B.2024; 12(42): 10877. CrossRef
Influence of PD‐L1 expression on the efficacy of EGFR‐TKIs in EGFR‐mutant non‐small cell lung cancer
Si‐Yu Lei, Hai‐Yan Xu, Hong‐Shuai Li, Ya‐Ning Yang, Fei Xu, Jun‐Ling Li, Zhi‐Jie Wang, Pu‐Yuan Xing, Xue‐Zhi Hao, Yan Wang
Thoracic Cancer.2023; 14(24): 2327. CrossRef
Association of PD‐L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR‐mutated NSCLC
Yusuke Hamakawa, Yoko Agemi, Aya Shiba, Toshiki Ikeda, Yuko Higashi, Masaharu Aga, Kazuhito Miyazaki, Yuri Taniguchi, Yuki Misumi, Yukiko Nakamura, Tsuneo Shimokawa, Yusuke Saigusa, Nobuaki Kobayashi, Hiroaki Okamoto, Takeshi Kaneko
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Yu-Wei Fang, Chieh-Yu Liu
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Edouard Dantoing, Nicolas Piton, Mathieu Salaün, Luc Thiberville, Florian Guisier
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Zahra Alipour, Kris Ann P Schultz, Ling Chen, Anne K Harris, Ivan A Gonzalez, John Pfeifer, D Ashley Hill, Mai He, Louis P Dehner
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Matthew Evans, Brendan O’Sullivan, Frances Hughes, Tina Mullis, Matthew Smith, Nicola Trim, Philippe Taniere
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PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer
Eriko Miyawaki, Haruyasu Murakami, Keita Mori, Nobuaki Mamesaya, Takahisa Kawamura, Haruki Kobayashi, Shota Omori, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Tateaki Naito, Toshiaki Takahashi
Japanese Journal of Clinical Oncology.2020; 50(5): 617. CrossRef
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Mai He, Brooj Abro, Madhurima Kaushal, Ling Chen, Tiffany Chen, Mercia Gondim, Weisi Yan, Julie Neidich, Louis P. Dehner, John D. Pfeifer
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Yoon Ah Cho, Yoon‐La Choi, Inwoo Hwang, Kyungjong Lee, Jong Ho Cho, Joungho Han
Thoracic Cancer.2020; 11(11): 3205. CrossRef
Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma
Jang Ho Cho, Hyun Ae Jung, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Jong-Mu Sun
Journal of Cancer Research and Clinical Oncology.2019; 145(5): 1341. CrossRef
The canonical TGF-β/Smad signalling pathway is involved in PD-L1-induced primary resistance to EGFR-TKIs in EGFR-mutant non-small-cell lung cancer
Yang Zhang, Yuanyuan Zeng, Ting Liu, Wenwen Du, Jianjie Zhu, Zeyi Liu, Jian-an Huang
Respiratory Research.2019;[Epub] CrossRef
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Lee, Kim, Sung, Lee, Han, Kim, Choi
International Journal of Molecular Sciences.2019; 20(19): 4794. CrossRef
Clinical and Molecular Predictors of PD-L1 Expression in Non–Small-Cell Lung Cancer: Systematic Review and Meta-analysis
Fausto Petrelli, Mariangela Maltese, Gianluca Tomasello, Barbara Conti, Karen Borgonovo, Mary Cabiddu, Mara Ghilardi, Michele Ghidini, Rodolfo Passalacqua, Sandro Barni, Matteo Brighenti
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Hyung Kyu Park, Mingi Kim, Minjung Sung, Seung Eun Lee, Yu Jin Kim, Yoon-La Choi
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Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: a meta-analysis
Bo Lan, Chengxi Ma, Chengyan Zhang, Shoujie Chai, Pingli Wang, Liren Ding, Kai Wang
Oncotarget.2018; 9(7): 7684. CrossRef
Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma
Byung Soo Lee, Dong Il Park, Da Hye Lee, Jeong Eun Lee, Min-kyung Yeo, Yeon Hee Park, Dae Sik Lim, Wonyoung Choi, Da Hye Lee, Geon Yoo, Han-byul Kim, Dahyun Kang, Jae Young Moon, Sung Soo Jung, Ju Ock Kim, Sang Yeon Cho, Hee Sun Park, Chaeuk Chung
Biochemical and Biophysical Research Communications.2017; 491(2): 493. CrossRef

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Effects and Mechanisms of Metformin on the Proliferation of Esophageal Cancer Cells In Vitro and In Vivo: Jian-Cai Tang, Rui An, Yi-Qing Jiang, Jian Yang; Cancer Res Treat. 2017;49(3):778-789. Published online November 11, 2016; DOI: https://doi.org/10.4143/crt.2015.485

Abstract PDF PubReader ePub

Purpose
The purpose of this study was to observe the effects of metformin on human esophageal cancer cell and to investigate its possible mechanisms.
Materials and Methods
Cell viability was detected by using a Cell Counting Kit-8, while cell cycle and apoptosis were assessed by flow cytometry and western blot was used to measure the expression of the related proteins. RNAi was used to knockout pyruvate kinase muscle isozyme 2 (PKM2). An Eca109 tumor model was established to evaluate the antitumor effect in vivo. Immunohistochemistry was determined based on the expression of PKM2 and Bim in tumor tissues. Tunnel was used to assess tumor cell apoptosis.
Results
Esophageal cancer cells viability was reduced after metformin treatment. The cell cycle was arrested in the G0/G1 phase, apoptosis was induced, caspase 3 was activated, caspase 9 was downregulated, and the pro-apoptotic protein Bim increased. Further study revealed that metformin could suppress the expression of insulin-like growth factor 1 receptor and its downstream proteins, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT/PKB), phosphorylation of AKT (pAKT), mammalian target of rapamycin (mTOR), p70S6K, and PKM2. Insulin-like growth factor 1 partly reversed metfromin-induced apoptosis and attenuated the repression effect of metfomin to PI3K, pAKT, and PKM2. Knockout PKM2 resulted in the activation of caspase 3, down-regulation of caspase 9, and increased expression of Bim. In the Eca109 xenograft model, metformin significantly reduced tumor growth. Furthermore, we found that metformin treatment increased the rate of apoptosis, down-regulation of PKM2, and up-regulation of Bim in tumor tissues.
Conclusion
Metformin restrained esophageal cancer cell proliferation partly by suppressing the PI3K/AKT/mTOR pathway.

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Hemin Ashayeri Ahmadabad, Somayeh Mohammadi Panah, Hojat Ghasemnejad‐Berenji, Shabnam Ghojavand, Morteza Ghasemnejad-Berenji, Mohammad Rafi Khezri
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Heliyon.2023; 9(6): e16678. CrossRef
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Bustanur Rosidi, Diana Priyatno, Teguh Pribadi Putra, Irawan Yusuf
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Mirian Galliote Morale, Rodrigo Esaki Tamura, Ileana Gabriela Sanchez Rubio
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Carsten Lange, Amanda Machado Weber, Ronny Schmidt, Christoph Schroeder, Thomas Strowitzki, Ariane Germeyer, Jae-Wook Jeong
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Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis
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Zengjia Liu, Guiju Hu, Yan Zhao, Zuorun Xiao, Mingzhe Yan, Mei Ren
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Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma: Hae Il Jung, Dongjun Jeong, Sanghee Ji, Tae Sung Ahn, Sang Ho Bae, Susie Chin, Jun Chul Chung, Hyung Chul Kim, Moon Soo Lee, Moo-Jun Baek; Cancer Res Treat. 2017;49(1):246-254. Published online July 7, 2016; DOI: https://doi.org/10.4143/crt.2016.066

Abstract PDF PubReader ePub

Purpose
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC.
Materials and Methods
Formalin-fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis.
Results
The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD-L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034).
Conclusion
The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted.

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Radiation-Induced Autophagy Contributes to Cell Death and Induces Apoptosis Partly in Malignant Glioma Cells: Guk Heui Jo, Oliver Bögler, Yong-Joon Chwae, Heon Yoo, Seung Hoon Lee, Jong Bae Park, Youn-Jae Kim, Jong Heon Kim, Ho-Shin Gwak; Cancer Res Treat. 2015;47(2):221-241. Published online August 29, 2014; DOI: https://doi.org/10.4143/crt.2013.159

Abstract PDF PubReader ePub

Purpose
Radiation-induced autophagy has been shown to play two different roles, in malignant glioma (MG) cells, cytocidal or cytoprotective. However, neither the role of radiation-induced autophagy for cell death nor the existence of autophagy-induced apoptosis, a well-known cell-death pathway after irradiation, has been verified yet. Materials and Methods We observed both temporal and dose-dependent response patterns of autophagy and apoptosis to radiation in MG cell lines. Additionally, we investigated the role of autophagy in apoptosis through knockdown of autophagy-related proteins. Results Autophagic activity measured by staining of acidic vesicle organelles and Western blotting of LC-3 protein increased in proportion to radiation dose from day 1 to 5 after irradiation. Apoptosis measured by annexin-V staining and Western blotting of cleaved poly(ADP-ribose) polymerase demonstrated relatively late appearance 3 days after irradiation that increased for up to 7 days. Blocking of pan-caspase (Z-VAD-FMK) did not affect apoptosis after irradiation, but silencing of Atg5 effectively reduced radiation-induced autophagy, which decreased apoptosis significantly. Inhibition of autophagy in Atg5 knockdown cells was shown to be beneficial for cell survival. Stable transfection of GFP-LC3 cells was observed after irradiation. Annexin-V was localized in cells bearing GFP-LC3 punctuated spots, indicating autophagy in immunofluorescence. Some of these punctuated GFP-LC3 bearing cells formed conglomerated spots and died in final phase. Conclusion These findings suggest that autophagy appears earlier than apoptosis after irradiation and that a portion of the apoptotic population that appears later is autophagy-dependent. Thus, autophagy is a pathway to cell death after irradiation of MG cells.

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The Effects of Insulin-like Growth Factor-I (IGF-I) in Mouse Lung Cancer Cells: Seung Min Kwak, Se Kyu Kim, Sung Kyu Kim, Chul Ho Cho; Cancer Res Treat. 2002;34(2):122-127. Published online April 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.2.122

Abstract PDF: PURPOSE
Insulin-like growth factor-I (IGF-I) is an important mitogen in many types of malignancies. The purpose of this study was to evaluate the role of the IGF system on cell proliferation and cell death in mouse lung cancer cell lines (3LL).
MATERIALS AND METHODS
Northern analysis was performed in 3LL cells. We evaluated the phosphorylation of IGF-I receptor (IGF-IR) with IGF-I stimulation. MTT assay was performed after treating 3LL cells with IGF-I and the treatment effect on cell death in the presence of anticancer drug was investigated.
RESULTS
Northern analysis revealed the presence of IGF-I and IGF-IR mRNA expression in 3LL cells. IGF-I increased cellular proliferation in serum free media. IGF-I also stimulated the tyrosine phosphorylation of two proteins: one, with a molecular mass of 95 kDa, was the beta-subunit of IGF-IR; the other, with an approximate molecular mass of 185 kDa, was originally identified as the insulin receptor substrate-I (IRS-I). IGF-I at a low concentration inhibited the cell death induced by adriamycin.
CONCLUSION
IGF-I, a mitogen through the phosphorylation of the IGF-IR beta-subunit, acts as a survival factor to inhibit cell death. Therefore, these findings suggest that IGF-I and IGF-IR are involved in both the cell proliferation and cell death associated with cancer cell growth.

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