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Frontiers in Medical Science Research, 2023, 5(11); doi: 10.25236/FMSR.2023.051103.

Normalizing Function of Vessels in Desmoplastic Histopathological Growth Pattern, a Way to Restore the Immune Microenvironment in the Liver Metastases


Yu Chen1, Jiancheng Li1, Hao Cai1, Houjun Jia2

Corresponding Author:
Houjun Jia

1Chongqing Medical University, Chongqing, 400016, China

2Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China


Solid tumors have the tendency to grow in normal tissue. By using hematoxylin and eosin (H&E) staining, the junction between solid tumors and normal tissue can be observed, revealing features such as vascular morphology. The histological growth pattern (HGP) of liver metastatic lesions can be categorized into two main types: alternative growth and connective tissue hyperplasia. Each subtype of HGP has distinct angiogenic patterns and immune cell infiltration statuses. The replacement histological growth pattern (r-HGP) grows directly around normal blood vessels without the need for neovascularization. Tumors with this pattern do not respond significantly to anti-angiogenic therapy or immunotherapy. On the other hand, the desmoplastic histological growth pattern (d-HGP) causes an inflammatory response in the junctional area between tumor cells and immune cells. The inflammation area promotes angiogenesis and suppresses immune cells. Controlled doses of anti-angiogenic therapy can improve vascular function in d-HGP and enhance the effect of tumor immunotherapy. However, this treatment option is only effective in d-HGP with disrupted vessels. Therefore, evaluating HGP in liver metastatic tumors is crucial before considering the combination of normalization of vascular function with immunotherapy.


Liver metastases, Histological Growth Pattern (HGP), Normalization of Vascular Function Immunotherapy, Bevacizumab

Cite This Paper

Yu Chen, Jiancheng Li, Hao Cai, Houjun Jia. Normalizing Function of Vessels in Desmoplastic Histopathological Growth Pattern, a Way to Restore the Immune Microenvironment in the Liver Metastases. Frontiers in Medical Science Research (2023) Vol. 5, Issue 11: 19-28. https://doi.org/10.25236/FMSR.2023.051103.


[1] van Dam P-J, van der Stok EP, Teuwen L-A, Van den Eynden GG, Illemann M, Frentzas S, et al. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. British Journal of Cancer. 2017;117:1427–1441.

[2] Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van den Heuvel E, et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. The Journal of Pathology. 2001;195:336–342.

[3] Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van den Heuvel E, Harris AL, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. British Journal of Cancer [Internet]. 2004 [cited 2023 Jun 8];90:1429–1436. Available from: https://pubmed. ncbi.nlm. nih. gov/15054467/

[4] Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nature Medicine [Internet]. 2016 [cited 2022 Dec 31];22:1294–1302. Available from: https://pubmed.ncbi.nlm.nih.gov/27748747/

[5] Van den Eynden GG, Bird NC, Majeed AW, Van Laere S, Dirix LY, Vermeulen PB. The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clinical & Experimental Metastasis. 2012;29:541–549.

[6] Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nature Reviews Immunology. 2011;11:702–711.

[7] Huang Y, Yuan J, Righi E, Kamoun WS, Marek Ancukiewicz, Nezivar J, et al. Vascular normalizing doses of anti-angiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences; 2012;109:17561–17566.

[8] Galjart B, Pieter M. H. Nierop, Eric, Robert, Höppener DJ, Sofie Daelemans, et al. Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases. Angiogenesis. 2019;22:355–368.

[9] Stylianopoulos T, Munn LL, Jain RK. Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends in Cancer [Internet]. 2018;4:292–319. Available from: https://pubmed.ncbi.nlm.nih.gov/29606314/

[10] Bataller R, Brenner DA. Liver fibrosis. Journal of Clinical Investigation [Internet]. 2005;115:209–218. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC546435/

[11] Katalin Dezső, Papp V, Edina Bugyik, Hargita Hegyesi, Géza Sáfrány, Csaba Bödör, et al. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology. 2012;56:1457–1467.

[12] Oertel M, Menthena A, Dabeva MD, Shafritz DA. Cell Competition Leads to a High Level of Normal Liver Reconstitution by Transplanted Fetal Liver Stem/Progenitor Cells. Gastroenterology. 2006; 130: 507–520.

[13] Wen Q, Huang M, Xie J, Liu R, Miao Q, Huang J, et al. lncRNA SYTL5-OT4 promotes vessel co-option by inhibiting the autophagic degradation of ASCT2. Drug Resist Updat. 2023;69:100975–100975.

[14] Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Høyer-Hansen G, et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Research [Internet]. 2013;73:2031–2043. Available from: https://pubmed.ncbi. nlm.nih. gov/ 23536564/

[15] Long J, Hu Z, Xue H, Wang Y, Chen J, Tang F, et al. Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2‐RhoA‐cofilin1 pathway. Cancer Sci. 2019;110:2357–2367.

[16] Ueda S, Saeki T, Osaki A, Yamane T, Ichiei Kuji. Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis. Angiogenesis. 2017;23:5769–5778.

[17] Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, et al. Vessel co‐option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Medicine. 2013; 2:427–436.

[18] Jayson GC, Kerbel R, Ellis LM, Harris AL. Anti-angiogenic therapy in oncology: current status and future directions. Lancet (London, England) [Internet]. England; 2016;388:518–529. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26853587

[19] Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, et al. Histopathologic-Based Prognostic Factors of Colorectal Cancers Are Associated With the State of the Local Immune Reaction. Journal of Clinical Oncology. 2011;29:610–618.

[20] Pieter M. H. Nierop, Höppener DJ, Buisman FE, Eric, Galjart B, Balachandran VP, et al. Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases. J Pathol Clin Res. 2021;8:48–64.

[21] Buisman FE, Eric, Galjart B, Vermeulen PB, Balachandran VP, Robert, et al. Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases. Clin Exp Metastasis. 2020;37:593–605.

[22] Heinemann V, Weikersthal von, Decker T, Kiani A, Kaiser FG, Salah-Edin Al-Batran, et al. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer. 2021;124:587–594.

[23] Halama N, Michel S, Kloor M, Zoernig I, Pommerencke T, von Knebel Doeberitz M, et al. The localization and density of immune cells in primary tumors of human metastatic colorectal cancer shows an association with response to chemotherapy. Cancer Immunity [Internet]. 2009 [cited 2023 Jun 8];9:1. Available from: https://pubmed.ncbi.nlm.nih.gov/19226101/

[24] Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab, in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Communications. 2016;7.

[25] Wu X, Giobbie-Hurder A, Liao X, Connelly C, Connolly EM, Li J, et al. Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy. Cancer Immunology Research [Internet]. 2017 [cited 2023 Jan 15];5:17–28. Available from: https://pubmed.ncbi.nlm.nih.gov/28003187/

[26] Taylor AW. Review of the activation of TGF-  in immunity. Journal of Leukocyte Biology. 2008; 85: 29–33.

[27] Calon A, Tauriello DVF, Batlle E. TGF-beta in CAF-mediated tumor growth and metastasis. Seminars in Cancer Biology [Internet]. 2014 [cited 2021 Oct 12];25:15–22. Available from: https://www.sciencedirect.com/science/article/pii/S1044579X14000054?via%3Dihub

[28] Strazza M, Inbar Azoulay-Alfaguter, Peled M, Smrcka AV, Skolnik EY, Srivastava S, et al. PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation. Natl Acad Sci. 2017; 114:2693–2698.

[29] Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). Journal of Experimental Medicine. 1996; 184:1101–1109.

[30] Crump MP. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. The EMBO Journal. 1997; 16:6996–7007.

[31] Baerts L, Waumans Y, Brandt I, Jungraithmayr W, Van der Veken P, Vanderheyden M, et al. Circulating Stromal Cell-Derived Factor 1α Levels in Heart Failure: A Matter of Proper Sampling. PloS One [Internet]. 2015 [cited 2023 Jun 8];10:e0141408. Available from: https://pubmed. ncbi.nlm. nih. gov/26544044/

[32] Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood [Internet]. 1998 [cited 2023 Jun 8];92:4150–4166. Available from: https://pubmed.ncbi.nlm.nih.gov/9834220/

[33] Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet A-L, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. The Journal of Experimental Medicine [Internet]. 2015 [cited 2021 Mar 24];212:139–148. Available from: https://www.ncbi.nlm.nih. gov/ pmc/articles/PMC4322048/

[34] Laarhoven van, Johannes H.A.M. Kaanders, Lok J, Wenny J.M. Peeters, P.F.J.W. Rijken, Wiering B, et al. Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. Int J Radiat Oncol Biol Phys. 2006;64:473–482.

[35] Maenhout SK, Thielemans K, Aerts JL. Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells. OncoImmunology. 2014;3:e956579.

[36] Jain Rakesh K. Anti-angiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia. Cancer Cell. 2014;26:605–622.

[37] Hagendoorn J, Tong R, Fukumura D, Lin Q, Lobo J, Padera TP, et al. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Research [Internet]. 2006 [cited 2023 Jun 8];66:3360–3364. Available from: https://pubmed. ncbi.nlm. nih.gov/16585153/

[38] Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, et al. Hypoxia: a key player in anti-tumor immune response. A Review in the Theme: Cellular Responses to Hypoxia. American Journal of Physiology-Cell Physiology. 2015;309:C569–79.

[39] Ju S, Wang F, Wang Y, Ju S. CSN8 is a key regulator in hypoxia-induced epithelial-mesenchymal transition and dormancy of colorectal cancer cells. Molecular Cancer [Internet]. 2020 [cited 2023 Jun 8]; 19:168. Available from: https://pubmed.ncbi.nlm.nih.gov/33261601/

[40] Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using anti-angiogenics: opportunities and challenges. Nature Reviews Clinical Oncology. 2018;15:325–340.

[41] Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nature Reviews Cancer [Internet]. 2016;16:447–462. Available from: https://www.nature.com/articles/nrc.2016.54

[42] Shurin MR, Umansky V. Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy. Journal of Clinical Investigation. 2022;132.

[43] Clever D, Roychoudhuri R, Constantinides MG, et al. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell. 2016;166(5):1117-1131.e14. doi:10.1016/j.cell.2016.07.032 tastatic niche. Cell [Internet]. 2016 [cited 2021 Apr 19];166:1117-1131.e14. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548538/

[44] Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8. Published 2020 Feb 7. doi:10.1038/s41392-020-0110-5

[45] Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nature Reviews Cancer [Internet]. 2011; 11:393–410. Available from: https://www.nature.com/articles/nrc3064

[46] Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature [Internet]. 1998; 394:485–490. Available from: https://www.nature.com/articles/28867

[47] Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, et al. Acidity Generated by the Tumor Microenvironment Drives Local Invasion. Cancer Research. 2013;73:1524–1535.

[48] Schito L, Semenza GL. Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends in Cancer. 2016;2:758–770.

[49] Philip B, Ito K, Moreno-Sánchez R, Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis [Internet]. 2013;34:1699–1707. Available from: https://pubmed. ncbi.nlm.nih.gov/23740838/

[50] Zhang J, Zhang Q, Lou Y, Fu Q, Chen Q, Wei T, et al. Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology (Baltimore, Md) [Internet]. 2018;67:1872–1889. Available from: https://pubmed.ncbi.nlm.nih.gov/29171040/

[51] Chauhan VP, Stylianopoulos T, Martin JD, Popović Z, Chen O, Kamoun WS, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nature Nanotechnology. 2012;7:383–388.

[52] Lorgis V, Maura G, Coppa G, Hassani K, Taillandier L, Chauffert B, et al. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. Journal of Neuro-Oncology [Internet]. 2012 [cited 2023 Jun 8];107:351–358. Available from: https://pubmed.ncbi.nlm.nih.gov/22076449/

[53] Kreisl TN, Smith P, Sul J, Salgado C, Iwamoto FM, Shih JH, et al. Continuous daily sunitinib for recurrent glioblastoma. Journal of Neuro-Oncology [Internet]. 2013 [cited 2023 Jun 8];111:41–48. Available from: https://pubmed.ncbi.nlm.nih.gov/23086433/

[54] Zhu AX, Abbas AR, de Galarreta MR, Guan Y, Lu S, Koeppen H, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nature Medicine [Internet]. 2022 [cited 2023 Jun 8];28:1599–1611. Available from: https://pubmed.ncbi.nlm.nih.gov/35739268/

[55] Chryplewicz A, Scotton J, Tichet M, Zomer A, Shchors K, Joyce JA, et al. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity. Cancer Cell [Internet]. 2022 [cited 2022 Sep 26];1111-1127. Available from: https://www. sciencedirect. com/science/article/pii/S1535610822003786

[56] Raghav K, Liu S, Overman MJ, Willett AF, Knafl M, Fu S-C, et al. Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma. Cancer Discovery [Internet]. 2021 [cited 2023 Jun 8];11:2738–2747. Available from: https://pubmed.ncbi.nlm.nih.gov/34261675/

[57] Yang Y-M, Hong P, Xu WW, He Q-Y, Li B. Advances in targeted therapy for esophageal cancer. Signal Transduction and Targeted Therapy [Internet]. 2020;5:1–11. Available from: https://www. nature. com/articles/s41392-020-00323-3#Tab2

[58] Yamaguchi J. Computed Tomographic Findings of Colorectal Liver Metastases Can Be Predictive for Recurrence After Hepatic Resection. Archives of Surgery. 2002;137:1294.

[59] Gilles Mentha, Sylvain Terraz, Morel P, Andres A, Emiliano Giostra, Roth A, et al. Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases. British Journal of Surgery. Wiley; 2008;96:95–103.

[60] Starmans MPA, Buisman FE, Renckens M, Willemssen FEJA, van der Voort SR, Groot Koerkamp B, et al. Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study. Clinical & Experimental Metastasis. 2021;38:483–494.

[61] Semelka RC, Hussain SM, Marcos HB, Woosley JT. Perilesional Enhancement of Hepatic Metastases: Correlation between MR Imaging and Histopathologic Findings—Initial Observations. Radiology. 2000; 215:89–94.