肿瘤相关成纤维细胞在卵巢癌恶性进展中的作用

徐 佳露, 曾 泓霖, 陈友 国*
苏州大学附属第一医院

摘要


卵巢癌是女性最常见的恶性肿瘤之一。该疾病存在发现晚、复发早、病死率高的特点。尽管随着临床治疗
手段的不断进步，卵巢癌患者的预后有所改善，但其具体发病机制仍未完全阐明，病死率依然居高不下。近年来，
肿瘤微环境（tumor microenvironment，TME）成为研究的热点，肿瘤相关成纤维细胞（cancer associated fibroblasts，
CAFs）作为其重要组成部分，被认为在卵巢癌的生物学进展中发挥着关键作用。本文就CAFs在卵巢癌TME中促进
细胞外基质重塑、信号通路激活、免疫抑制、血管生成、耐药等方面进行综述。

关键词


卵巢癌；肿瘤微环境；肿瘤相关成纤维细胞；细胞外基质重塑；免疫抑制

全文:

PDF


参考


[1]Bray F, Laversanne M, Sung H, et al. Global cancer

statistics 2022: GLOBOCAN estimates of incidence and

mortality worldwide for 36 cancers in 185 countries. CA

Cancer J Clin 2024; 74(3): 229-63.

[2]Lheureux S, Braunstein M, Oza AM. Epithelial

ovarian cancer: Evolution of management in the era of

precision medicine. CA Cancer J Clin 2019; 69(4): 280-304.

[3]陈雨莲，臧荣余.卵巢癌免疫检查点抑制剂应用的

现状与挑战.中国实用妇科与产科杂志，2024；40（11）：

1078-82.

[4]Paget S. The distribution of secondary growths in

cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8(2).

[5]Theocharis AD, Skandalis SS, Gialeli C, Karamanos

NK. Extracellular matrix structure. Adv Drug Deliv Rev

2016; 97.

[6]Arina A, Idel C, Hyjek EM, et al. Tumor-associated

fibroblasts predominantly come from local and not circulating

precursors. Proc Natl Acad Sci U S A 2016; 113(27): 7551-6.

[7]Zhang M, Chen Z, Wang Y, Zhao H, Du Y. The

Role of Cancer-Associated Fibroblasts in Ovarian Cancer.Cancers (Basel) 2022; 14(11).

[8]Virchow R. Die Cellularpathologie in ihrer

Begründung auf physiologische und pathologische

Gewebelehre: Good Press; 2020.

[9]Chen X, Song E. Turning foes to friends: targeting

cancer-associated fibroblasts. Nat Rev Drug Discov 2019;

18(2).

[10]Ko SY, Barengo N, Ladanyi A, et al. HOXA9

promotes ovarian cancer growth by stimulating cancerassociated fibroblasts. J Clin Invest 2012; 122(10): 3603-17.

[11]Weber CE, Kothari AN, Wai PY, et al. Osteopontin

mediates an MZF1-TGF-β1-dependent transformation of

mesenchymal stem cells into cancer-associated fibroblasts in

breast cancer. Oncogene 2015; 34(37): 4821-33.

[12]De Craene B, Berx G. Regulatory networks defining

EMT during cancer initiation and progression. Nat Rev

Cancer 2013; 13(2).

[13]Piera-Velazquez S, Jimenez SA. Endothelial to

Mesenchymal Transition: Role in Physiology and in the

Pathogenesis of Human Diseases. Physiol Rev 2019; 99(2):

1281-324.

[14]Nurmik M, Ullmann P, Rodriguez F, Haan S,

Letellier E. In search of definitions: Cancer-associated

fibroblasts and their markers. Int J Cancer 2020; 146(4): 895-

905.

[15]Givel A-M, Kieffer Y, Scholer-Dahirel A, et

al. miR200-regulated CXCL12β promotes fibroblast

heterogeneity and immunosuppression in ovarian cancers. Nat

Commun 2018; 9(1): 1056.

[16]Costa A, Kieffer Y, Scholer-Dahirel A, et al.

Fibroblast Heterogeneity and Immunosuppressive Environment

in Human Breast Cancer. Cancer Cell 2018; 33(3).

[17]Elyada E, Bolisetty M, Laise P, et al. Cross-Species

Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma

Reveals Antigen-Presenting Cancer-Associated Fibroblasts.

Cancer Discov 2019; 9(8): 1102-23.

[18]Pelon F, Bourachot B, Kieffer Y, et al. Cancerassociated fibroblast heterogeneity in axillary lymph nodes

drives metastases in breast cancer through complementary

mechanisms. Nat Commun 2020; 11(1): 404.

[19]Mathieson L, Koppensteiner L, Dorward DA,

O’Connor RA, Akram AR. Cancer-associated fibroblasts

expressing fibroblast activation protein and podoplanin in

non-small cell lung cancer predict poor clinical outcome. Br J

Cancer 2024; 130(11): 1758-69.

[20]Izar B, Tirosh I, Stover EH, et al. A single-cell

landscape of high-grade serous ovarian cancer. Nat Med

2020; 26(8): 1271-9.

[21]Kieffer Y, Hocine HR, Gentric G, et al. Single-Cell

Analysis Reveals Fibroblast Clusters Linked to Immunotherapy

Resistance in Cancer. Cancer Discov 2020; 10(9): 1330-51.

[22]Öhlund D, Handly-Santana A, Biffi G, et al. Distinct

populations of inflammatory fibroblasts and myofibroblasts in

pancreatic cancer. J Exp Med 2017; 214(3): 579-96.

[23]Avery D, Govindaraju P, Jacob M, Todd L,

Monslow J, Puré E. Extracellular matrix directs phenotypic

heterogeneity of activated fibroblasts. Matrix Biol 2018; 67.

[24]Desbois M, Wang Y. Cancer-associated fibroblasts:

Key players in shaping the tumor immune microenvironment.

Immunol Rev 2021; 302(1): 241-58.

[25]Hornburg M, Desbois M, Lu S, et al. Single-cell

dissection of cellular components and interactions shaping the

tumor immune phenotypes in ovarian cancer. Cancer Cell

2021; 39(7).

[26]Kalluri R. The biology and function of fibroblasts in

cancer. Nat Rev Cancer 2016; 16(9): 582-98.

[27]Hanahan D, Weinberg RA. Hallmarks of cancer: the

next generation. Cell 2011; 144(5): 646-74.

[28]Levental KR, Yu H, Kass L, et al. Matrix

crosslinking forces tumor progression by enhancing integrin

signaling. Cell 2009; 139(5): 891-906.

[29]Jiang X, Hu J, Wu Z, et al. Protein Phosphatase 2A

Mediates YAP Activation in Endothelial Cells Upon VEGF

Stimulation and Matrix Stiffness. Front Cell Dev Biol 2021; 9:

675562.

[30]Sherman MH, Yu RT, Engle DD, et al. Vitamin

D receptor-mediated stromal reprogramming suppresses

pancreatitis and enhances pancreatic cancer therapy. Cell

2014; 159(1): 80-93.

[31]Yeung T-L, Leung CS, Wong K-K, et al. TGF-β

modulates ovarian cancer invasion by upregulating CAFderived versican in the tumor microenvironment. Cancer Res2013; 73(16): 5016-28.

[32]Sahai E, Astsaturov I, Cukierman E, et al. A

framework for advancing our understanding of cancerassociated fibroblasts. Nat Rev Cancer 2020; 20(3): 174-86.

[33]Wu Y-H, Huang Y-F, Chang T-H, et al.

COL11A1 activates cancer-associated fibroblasts by

modulating TGF-β3 through the NF-κB/IGFBP2 axis in

ovarian cancer cells. Oncogene 2021; 40(26): 4503-19.

[34]Chandra Jena B, Sarkar S, Rout L, Mandal M.

The transformation of cancer-associated fibroblasts: Current

perspectives on the role of TGF-β in CAF mediated tumor

progression and therapeutic resistance. Cancer Lett 2021; 520:

222-32.

[35]Al-Ansari MM, Al-Saif M, Arafah M, et al. Clinical

and functional significance of tumor/stromal ATR expression

in breast cancer patients. Breast Cancer Res 2020; 22(1): 49.

[36]Lau T-S, Chung TK-H, Cheung T-H, et al.

Cancer cell-derived lymphotoxin mediates reciprocal tumourstromal interactions in human ovarian cancer by inducing

CXCL11 in fibroblasts. J Pathol 2014; 232(1): 43-56.

[37]Pei L, Liu Y, Liu L, et al. Roles of cancer-associated

fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for

solid cancers. Mol Cancer 2023; 22(1): 29.

[38]Feig C, Jones JO, Kraman M, et al. Targeting

CXCL12 from FAP-expressing carcinoma-associated

fibroblasts synergizes with anti-PD-L1 immunotherapy in

pancreatic cancer. Proc Natl Acad Sci U S A 2013; 110(50):

20212-7.

[39]Zhang H, Jiang R, Zhou J, et al. CTL Attenuation

Regulated by PS1 in Cancer-Associated Fibroblast. Front

Immunol 2020; 11: 999.

[40]Zhang Y, Tang H, Cai J, et al. Ovarian cancerassociated fibroblasts contribute to epithelial ovarian carcinoma

metastasis by promoting angiogenesis, lymphangiogenesis and

tumor cell invasion. Cancer Lett 2011; 303(1): 47-55.

[41]Li P, Zhang H, Chen T, Zhou Y, Yang J, Zhou

J. Cancer-associated fibroblasts promote proliferation,

angiogenesis, metastasis and immunosuppression in gastric

cancer. Matrix Biol 2024; 132: 59-71.

[42]Dasari S, Fang Y, Mitra AK. Cancer Associated

Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer

Progression. Cancers (Basel) 2018; 10(11).

[43]Zhou B, Sun C, Li N, et al. Cisplatin-induced

CCL5 secretion from CAFs promotes cisplatin-resistance in

ovarian cancer via regulation of the STAT3 and PI3K/Akt

signaling pathways. Int J Oncol 2016; 48(5): 2087-97.

[44]Liu J, Liu C, Ma Y, et al. STING inhibitors sensitize

platinum chemotherapy in ovarian cancer by inhibiting the

CGAS-STING pathway in cancer-associated fibroblasts

(CAFs). Cancer Lett 2024; 588: 216700.


Refbacks

  • 当前没有refback。