Review

Cancer-associated fibroblasts of colorectal cancer and their markers: updates, challenges and translational outlook

*Author for correspondence: Tel.: +609 7676 794;

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia

Search for more papers by this author

Adli Ali

https://orcid.org/0000-0001-5615-5966

Department of Paediatrics, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Wilayah Persekutuan, 56000 Kuala Lumpur, Malaysia

Department of Paediatrics, Oxford University, Level 2, Children’s Hospital, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

Search for more papers by this author

Published Online:20 Jul 2020https://doi.org/10.2217/fon-2020-0384

View article

Abstract

Accumulation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment is associated with poor prognosis and recurrence of colorectal cancer (CRC). Despite their prominent roles in colorectal carcinogenesis, there is a lack of robust and specific markers to classify the heterogeneous and highly complex CAF populations. This has resulted in confusing and misleading definitions of CAFs in cancer niche. Advancements in molecular biology approaches have open doors to reliable CAF marker detection methods in various solid tumors. These discoveries would contribute to more efficient screening, monitoring and targeted therapy of CRC thus potentially will reduce cancer morbidity and mortality rates. This review highlights current scenarios, dilemma, translational potentials of CAF biomarker and future therapeutic applications involving CAF marker identification in CRC.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Bray F, Ferlay J, Soerjomataram I et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
MedlineGoogle Scholar
2. Brown S, Pineda C, Xin T et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548(7667), 334–337 (2017).
Medline CASGoogle Scholar
3. Wu J, Liang C, Chen M, Su W. Association between tumor-stroma ratio and prognosis in solid tumor patients: a systematic review and meta-analysis. Oncotarget 7(42), 68954–68965 (2016).
MedlineGoogle Scholar
4. Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16(9), 582–598 (2016). •• Details review on fibroblast population in tumor by well-known researcher in the field of tumor microenvironment.
Medline CASGoogle Scholar
5. LeBlue VS, Kalluri R. A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis. Model. Mech. 11(4), dmm029447 (2018).
MedlineGoogle Scholar
6. Guinney J, Dienstmann R, Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21(11), 1350–1356 (2015).
Medline CASGoogle Scholar
7. Isella C, Terrasi A, Bellomo S et al. Stromal contribution to the colorectal cancer transcriptome. Nat. Genet. 47(4), 312–319 (2015).
Medline CASGoogle Scholar
8. Becht E, de Reyniès A, Giraldo NA et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22(16), 4057–4066 (2016).
Medline CASGoogle Scholar
9. Xiong Y, Wang Y, Tiruthani K. Tumor immune microenvironment and nano-immunotherapeutics in colorectal cancer. Nanomedicine 21, 102034 (2019).
Medline CASGoogle Scholar
10. Gieniec KA, Butler LM, Worthley DL et al. Cancer-associated fibroblasts – heroes or villains? Br. J. Cancer 121(4), 293–302 (2019).
MedlineGoogle Scholar
11. Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv. Drug Deliv. Rev. 99(Pt B), 186–196 (2016).
Medline CASGoogle Scholar
12. Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel). 7(4), 2443–2458 (2015).
MedlineGoogle Scholar
13. Sahai E, Astsaturov I, Cukierman E et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20(3), 174–186 (2020). •• Comprehensive review and update on cancer-associated fibroblast’s (CAF) biology in cancer.
Medline CASGoogle Scholar
14. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59(19), 5002–5011 (1999). •• Earlier publication on characterization of activated and normal fibroblasts.
Medline CASGoogle Scholar
15. Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 4, 62 (2014). •• Documentation of major CAF marker expression namely alpha smooth muscle actin expression in CAFs compared with fibroblasts in normal tissue.
MedlineGoogle Scholar
16. Bochaton-Piallat ML, Gabbiani G, Hinz B. The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Res. 5, 752 (2016).
Google Scholar
17. De Wever O, Nguyen QD, Van Hoorde L et al. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 18(9), 1016–1018 (2004).
MedlineGoogle Scholar
18. Foster CT, Gualdrini F, Treisman R. Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics. Genes Dev. 31(23–24), 2361–2375 (2017).
Medline CASGoogle Scholar
19. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3(5), 349–363 (2002). •• Important paper on biology of myofibroblast/activated fibroblasts.
Medline CASGoogle Scholar
20. Strell C, Paulsson J, Jin SB et al. Impact of epithelial–stromal interactions on peritumoral fibroblasts in ductal carcinoma in situ. J. Natl Cancer Inst. 111(9), 983–995 (2019).
MedlineGoogle Scholar
21. Albrengues J, Bertero T, Grasset E et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204 (2015).
Medline CASGoogle Scholar
22. Avery D, Govindaraju P, Jacob M, Todd L, Monslow J, Puré E. Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. Matrix Biol. 67, 90–106 (2018).
Medline CASGoogle Scholar
23. Arina A, Idel C, Hyjek EM et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl Acad. Sci. USA 113(27), 7551–7556 (2016).
Medline CASGoogle Scholar
24. Kretzschmar K, Weber C, Driskell RR, Calonje E, Watt FM. Compartmentalized epidermal activation of β-catenin differentially affects lineage reprogramming and underlies tumor heterogeneity. Cell Rep. 14(2), 269–281 (2016).
Medline CASGoogle Scholar
25. Raz Y, Cohen N, Shani O et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J. Exp. Med. 215(12), 3075–3093 (2018).
Medline CASGoogle Scholar
26. Mukaida N, Sasaki S. Fibroblasts, an inconspicuous but essential player in colon cancer development and progression. World J. Gastroenterol. 22(23), 5301–5316 (2016).
Medline CASGoogle Scholar
27. Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: cancer-associated fibroblasts and their markers. Int. J. Cancer 146(4), 895–905 (2020).
Medline CASGoogle Scholar
28. Moore-Smith LD, Isayeva T, Lee JH, Frost A, Ponnazhagan S. Silencing of TGF-β1 in tumor cells impacts MMP-9 in tumor microenvironment. Sci. Rep. 7(1), 8678 (2017).
MedlineGoogle Scholar
29. Yang X, Li YD, Zou LQ, Zhu ZF. Role of exosomes in crosstalk between cancer-associated fibroblasts and cancer cells. Front. Oncol. 9, 356 (2019).
MedlineGoogle Scholar
30. Tao L, Huang G, Song H, Chen Y, Chen L. Cancer associated fibroblasts: an essential role in the tumor microenvironment. Oncol. Lett. 14(3), 2611–2620 (2017).
MedlineGoogle Scholar
31. Gonzalez-Zubeldia I, Dotor J, Redrado M et al. Co-migration of colon cancer cells and CAFs induced by TGFβ1 enhances liver metastasis. Cell Tissue Res. 359(3), 829–839 (2015).
Medline CASGoogle Scholar
32. Takatsuna M, Morohashi S, Yoshizawa T et al. Myofibroblast distribution is associated with invasive growth types of colorectal cancer. Oncol. Rep. 36(6), 3154–3160 (2016).
MedlineGoogle Scholar
33. Liu T, Zhou L, Li D, Andl T, Zhang Y. Cancer-associated fibroblasts build and secure the tumor microenvironment. Front. Cell Dev. Biol. 7, 60 (2019).
MedlineGoogle Scholar
34. Glentis A, Oertle P, Mariani P et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8(1), 924 (2017).
MedlineGoogle Scholar
35. Monteran L, Erez N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 10, 1835 (2019).
Medline CASGoogle Scholar
36. Öhlund D, Handly-Santana A, Biffi G et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214(3), 579–596 (2017).
Medline CASGoogle Scholar
37. Tommelein J, Verset L, Boterberg T, Demetter P, Bracke M, De Wever O. Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front. Oncol. 5, 63 (2015).
MedlineGoogle Scholar
38. Flint TR, Janowitz T, Connell CM et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016).
Medline CASGoogle Scholar
39. Zhang R, Qi F, Zhao F et al. Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis. 10(4), 273 (2019).
MedlineGoogle Scholar
40. Malta TM, Sokolov A, Gentles AJ et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173(2), 338–354.e315 (2018).
Medline CASGoogle Scholar
41. Basu S, Haase G, Ben-Ze'ev A. Wnt signaling in cancer stem cells and colon cancer metastasis. F1000Res. 5, 699 (2016).
Google Scholar
42. Nair N, Calle AS, Zahra MH et al. A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci. Rep. 7(1), 6838 (2017).
MedlineGoogle Scholar
43. Ren J, Ding L, Zhang D et al. Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics 8(14), 3932–3948 (2018).
Medline CASGoogle Scholar
44. Izumi D, Toden S, Ureta E et al. TIAM1 promotes chemoresistance and tumor invasiveness in colorectal cancer. Cell Death Dis. 10(4), 267 (2019).
MedlineGoogle Scholar
45. Kugeratski FG, Atkinson SJ, Neilson LJ et al. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Sci. Signal. 12(567), pii: eaan8247 (2019).
Google Scholar
46. Madsen CD, Pedersen JT, Venning FA et al. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumor stiffness and metastasis. EMBO Rep. 16(10), 1394–1408 (2015).
Medline CASGoogle Scholar
47. Drebert Z, MacAskill M, Doughty-Shenton D et al. Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor. Vascul. Pharmacol. 89, 19–30 (2017).
Medline CASGoogle Scholar
48. Santi A, Kugeratski FG, Zanivan S. Cancer associated fibroblasts: the architects of stroma remodeling. Proteomics 18(5–6), e1700167 (2018).
MedlineGoogle Scholar
49. Sasaki K, Sugai T, Ishida K et al. Analysis of cancer-associated fibroblasts and the epithelial-mesenchymal transition in cutaneous basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Hum. Pathol. 79, 1–8 (2018).
Medline CASGoogle Scholar
50. Pereira BA, Vennin C, Papanicolaou M et al. CAF subpopulations: a new reservoir of stromal targets in pancreatic cancer. Trends Cancer 5(11), 724–741 (2019).
MedlineGoogle Scholar
51. Li H, Courtois ET, Sengupta D et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49(5), 708–718 (2017).
Medline CASGoogle Scholar
52. Costa A, Kieffer Y, Scholer-Dahirel A et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).
Medline CASGoogle Scholar
53. Rettig WJ, Garin-Chesa P, Healey JH et al. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 53(14), 3327–3335 (1993). •• Discovery of one of the two major marker, namely fibroblast activation protein for activated stroma in solid tumor.
Medline CASGoogle Scholar
54. Cao F, Wang S, Wang H, Tang W. Fibroblast activation protein-α in tumor cells promotes colorectal cancer angiogenesis via the Akt and ERK signaling pathways. Mol. Med. Rep. 17(2), 2593–2599 (2018).
Medline CASGoogle Scholar
55. Sandberg TP, Stuart MPME, Oosting J et al. Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer. BMC Cancer 19(1), 284 (2019).
MedlineGoogle Scholar
56. Nishishita R, Morohashi S, Seino H et al. Expression of cancer-associated fibroblast markers in advanced colorectal cancer. Oncol. Lett. 15(5), 6195–6202 (2018).
MedlineGoogle Scholar
57. Lynch MD, Watt FM. Fibroblast heterogeneity: implications for human disease. J. Clin. Invest. 128(1), 26–35 (2018).
MedlineGoogle Scholar
58. Park CK, Jung WH, Koo JS. Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. Breast Cancer Res. Treat. 159(9), 55–69 (2016).
Medline CASGoogle Scholar
59. Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun. Signal. 11, 97 (2013).
MedlineGoogle Scholar
60. Hsia LT, Ashley N, Ouaret D, Wang LM, Wilding J, Bodmer WF. Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers. Proc. Natl Acad. Sci. USA 113(15), E2162–E2171 (2016).
Medline CASGoogle Scholar
61. Kinchen J, Chen HH, Parikh K et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175(2), 372–386 (2018).
Medline CASGoogle Scholar
62. Keller DS, Windsor A, Cohen R, Chand M. Colorectal cancer in inflammatory bowel disease: review of the evidence. Tech. Coloproctol. 23(1), 3–13 (2019).
Medline CASGoogle Scholar
63. Schulze AB, Schmidt LH, Heitkötter B et al. Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I–III NSCLC. Thorac. Cancer 11(1), 120–129 (2020).
Medline CASGoogle Scholar
64. Maehira H, Miyake T, Iida H et al. Vimentin expression in tumor environment predicts survival in pancreatic ductal adenocarcinoma: heterogeneity in fibroblast population. Ann. Surg. Oncol. 26(13), 4791–4804 (2019).
MedlineGoogle Scholar
65. Son GM, Kwon MS, Shin DH, Shin N, Ryu D, Kang CD. Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine (Baltimore) 98(18), e15164 (2019).
MedlineGoogle Scholar
66. Horman SR, To J, Lamb J et al. Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets. Oncotarget 8(59), 99913–99930 (2017).
MedlineGoogle Scholar
67. Tang F, Barbacioru C, Wang Y et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat. Methods 6(5), 377–382 (2009). • First description of transcriptome analysis at single cell level.
Medline CASGoogle Scholar
68. Hwang B, Lee JH, Bang D. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp. Mol. Med. 50(8), 96 (2018).
MedlineGoogle Scholar
69. Wilkins MR, Sanchez JC, Gooley AA et al. Progress with proteome projects: why all proteins expressed by a genome should be identified and how to do it. Biotechnol. Genet. Eng. Rev. 13, 19–50 (1996). • First group of researchers to introduce the concept of ‘proteome’.
Medline CASGoogle Scholar
70. Aslam B, Basit M, Nisar MA, Khurshid M, Rasool MH. Proteomics: technologies and their applications. J. Chromatogr. Sci. 55(2), 182–196 (2017).
Medline CASGoogle Scholar
71. Manousopoulou A, Hayden A, Mellone M et al. Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma. Br. J. Cancer 118(9), 1200–1207 (2018).
Medline CASGoogle Scholar
72. Nguyen EV, Pereira BA, Lawrence MG et al. Proteomic profiling of human prostate cancer-associated fibroblasts (CAF) reveals LOXL2-dependent regulation of the tumor microenvironment. Mol. Cell. Proteomics 18(7), 1410–1427 (2019).
Medline CASGoogle Scholar
73. Qiao J, Fang CY, Chen SX et al. Stroma derived COL6A3 is a potential prognosis marker of colorectal carcinoma revealed by quantitative proteomics. Oncotarget 6(30), 29929–29946 (2015).
MedlineGoogle Scholar
74. Torres S, Garcia-Palmero I, Herrera M et al. LOXL2 is highly expressed in cancer-associated fibroblasts and associates to poor colon cancer survival. Clin. Cancer Res. 21(21), 4892–4902 (2015).
Medline CASGoogle Scholar
75. Karagiannis G, Musrap N, Saraon P et al. Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression. Biol. Chem. 396(2), 163–183 (2015).
Medline CASGoogle Scholar
76. Drev D, Bileck A, Erdem ZN et al. Proteomic profiling identifies markers for inflammation-related tumor–fibroblast interaction. Clin. Proteom. 14, 33 (2017).
MedlineGoogle Scholar
77. Rai A, Greening DW, Chen M, Xu R, Ji H, Simpson RJ. Exosomes derived from human primary and metastatic colorectal cancer cells contribute to functional heterogeneity of activated fibroblasts by reprogramming their proteome. Proteomics 19(8), 1800148 (2019).
Google Scholar
78. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann. Gastroenterol. 27(1), 9–14 (2014).
MedlineGoogle Scholar
79. Carethers JM, Jung BH. Genetics and genetic markers in sporadic colorectal cancer. Gastroenterology 149(5), 1177–1190 (2015).
Medline CASGoogle Scholar
80. Calon A, Lonardo E, Berenguer-Llergo A et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 47(4), 320–329 (2015).
Medline CASGoogle Scholar
81. Kather JN, Charoentong P, Zoernig I, Jaeger D, Halama N. Prognostic value of histopathological tumor-stroma ratio and a stromal gene expression signature in human solid tumors. J. Clin. Oncol. 36(Suppl. 15), e24113–e24113 (2018).
Google Scholar
82. Verset L, Tommelein X, Lopez M et al. Impact of neoadjuvant therapy on cancer-associated fibroblasts in rectal cancer. Radiother. Oncol. 116(3), 449–454 (2015).
MedlineGoogle Scholar
83. Wei SC, Yang J. Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition. Trends Cell Biol. 26(2), 111–120 (2016).
Medline CASGoogle Scholar
84. Paulsson J, Micke P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin. Cancer Biol. 25, 61–68 (2014).
Medline CASGoogle Scholar
85. Dourado MR, Guerra ENS, Salo T, Lambert DW, Coletta RD. Prognostic value of the immunohistochemical detection of cancer-associated fibroblasts in oral cancer: a systematic review and meta-analysis. J. Oral Pathol. Med. 47(5), 443–453 (2018).
Medline CASGoogle Scholar
86. Franco-Barraza J, Francescone R, Luong T et al. Matrix-regulated integrin α_vβ₅ maintains α₅β₁-dependent desmoplastic traits prognostic of neoplastic recurrence. Elife 6, e20600 (2017).
MedlineGoogle Scholar
87. Mellone M, Hanley CJ, Thirdborough S et al. Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis. Aging (Albany NY). 9(1), 114–132 (2016).
MedlineGoogle Scholar
88. Dienstmann R, Villacampa G, Sveen A et al. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann. Oncol. 30(10), 1622–1629 (2019).
Medline CASGoogle Scholar
89. Maris P, Blomme A, Palacios AP et al. Asporin is a fibroblast-derived TGF-β1 inhibitor and a tumor suppressor associated with good prognosis in breast cancer. PLoS Med. 12(9), e1001871 (2015).
MedlineGoogle Scholar
90. Vazquez-Villa F, Garcia-Ocana M, Galvan JA et al. COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression. Tumor Biol. 36(4), 2213–2222 (2015).
Medline CASGoogle Scholar
91. Su C, Zhao J, Hong X, Yang S, Jiang Y, Hou J. Microarray-based analysis of COL11A1 and TWIST1 as important differentially-expressed pathogenic genes between left and right-sided colon cancer. Mol. Med. Rep. 20(5), 4202–4214 (2019).
Medline CASGoogle Scholar
92. Liu T, Han C, Wang S et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 12(1), 86 (2019).
Medline CASGoogle Scholar
93. Zeltz C, Primac I, Erusappan P, Alam J, Noel A, Gullberg D. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Semin. Cancer Biol. 62, 166–181 (2020).
Medline CASGoogle Scholar
94. Boudjadi S, Bernatchez G, Sénicourt B et al. Involvement of the Integrin α1β1 in the progression of colorectal cancer. Cancers 9(8), 96 (2017).
Google Scholar
95. Harryvan TJ, Verdegaal EME, Hardwick JCH, Hawinkels LJAC, van der Burg SH. Targeting of the cancer-associated fibroblast-T-cell axis in solid malignancies. J. Clin. Med. 8(11), 1989 (2019).
CASGoogle Scholar
96. Zhou Y, Xia L, Wang H et al. Cancer stem cells in progression of colorectal cancer. Oncotarget 9(70), 33403–33415 (2017).
MedlineGoogle Scholar
97. Lo A, Wang LS, Scholler J et al. Tumor promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75(14), 2800–2810 (2015).
Medline CASGoogle Scholar
98. Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR. Targeting tumor microenvironment for cancer therapy. Int. J. Mol. Sci. 20(4), 840 (2019).
Medline CASGoogle Scholar

Vol. 16, No. 29

Metrics

Downloaded 615 times

History

Received 21 April 2020

Accepted 22 June 2020

Published online 20 July 2020

Published in print October 2020

Information

Keywords

Author contributions

Both authors (M Musa and A Ali) have made substantial contributions to the conception or design of the work, drafting the work or revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial and competing interests disclosure

This work was supported by Short Term Research Grant, Universiti Sains Malaysia (USM) (grant number: 304/PPSP/6315409). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download