从遗传异质性认识口腔鳞癌的侵袭过程

doi:10.19438/j.cjoms.2022.02.017

摘要/Abstract

摘要： 口腔鳞癌侵袭前沿是肿瘤侵袭过程中形成的具有特征性病理结构的肿瘤区域。理解肿瘤的侵袭过程,可以通过研究侵袭前沿的形成过程来实现。侵袭前沿和肿瘤内部之间存在遗传异质性,肿瘤区域之间存在一定的克隆进化关系。在遗传学水平认识肿瘤侵袭,有赖于对侵袭前沿和肿瘤内部之间克隆结构组成及克隆进化关系的揭示。在此过程中,还可获知在肿瘤侵袭中发挥重要作用的遗传学事件,这些遗传学事件可能成为潜在的治疗靶点或侵袭相关生物标志物。口腔鳞癌侵袭过程的克隆演化路径具有肿瘤间异质性,对其他癌种的相关研究也发现了这种肿瘤间异质性,进一步揭示了侵袭相关亚克隆的遗传演化及亚克隆间的相互作用。本文着眼于从遗传学角度揭示口腔鳞癌的侵袭过程,结合其他癌种的相关研究,对肿瘤侵袭过程中的关键遗传学事件、遗传异质性以及克隆演进做一综述。

关键词: 口腔鳞癌, 肿瘤侵袭, 肿瘤侵袭前沿, 遗传异质性, 克隆进化

Abstract: The invasive front of oral cancer is a region characterized by detached mesenchymal-like tumor cells or cell groups. The process of the formation of the invasive front should be interrogated in order to understand tumor invasion. A certain degree of intratumor heterogeneity and clonal relationship exists between the tumor body and the invasive front. Understanding tumor invasion at genetic level requires revealing the clonal structure as well as the evolutionary relationship between the tumor body and the invasive front. The key genetic events driving tumor invasion can also be detected by reconstructing the clonal structure of the two tumor regions, on the basis of which potential therapeutic targets or biomarkers in invasion can be identified. The evolutionary trajectories in the invasion process of oral squamous cell carcinoma (OSCC) showed a great deal of intertumor heterogeneity. Researches in other cancers also found intertumor heterogeneity in the evolutionary patterns and further revealed the evolutionary process of invasive subclones and interactions between subclones. This review aimed at understanding tumor invasion in OSCC from a genetic perspective and extending our understanding of the key genetic events, genetic heterogeneity and clonal evolution during tumor invasion through evaluation of current knowledge in tumor invasion in other cancer types.

Key words: Oral squamous cell carcinoma, Tumor invasion, Invasive front, Genetic heterogeneity, Clonal evolution

中图分类号:

R739.8

瞿楚翔, 孙树洋, 张志愿. 从遗传异质性认识口腔鳞癌的侵袭过程[J]. 中国口腔颌面外科杂志, 2022, 20(2): 193-197.

QU Chu-xiang, SUN Shu-yang, ZHANG Zhi-yuan. Understanding oral cancer invasion from the perspective of genetic heterogeneity[J]. China J Oral Maxillofac Surg, 2022, 20(2): 193-197.

参考文献

[1] Ho CM, Lam KH, Wei WI, et al.Occult lymph node metastasis in small oral tongue cancers[J]. Head Neck, 1992, 14(5): 359-363.
[2] Ganly I, Patel S, Shah J.Early stage squamous cell cancer of the oral tongue-clinicopathologic features affecting outcome[J]. Cancer, 2012, 118(1): 101-111.
[3] Yamakawa N, Kirita T, Umeda M, et al.Tumor budding and adjacent tissue at the invasive front correlate with delayed neck metastasis in clinical early-stage tongue squamous cell carcinoma[J]. J Surg Oncol, 2019, 119(3): 370-378.
[4] Bryne M, Koppang HS, Lilleng R, et al.New malignancy grading is a better prognostic indicator than Broders' grading in oral squamous cell carcinomas[J]. J Oral Pathol Med, 1989, 18(8): 432-437.
[5] Heppner GH.Tumor heterogeneity[J]. Cancer Res, 1984, 44(6): 2259-2265.
[6] Sakr RA, Weigelt B, Chandarlapaty S, et al.PI3K pathway activation in high-grade ductal carcinoma in situ-implications for progression to invasive breast carcinoma[J]. Clin Cancer Res, 2014, 20(9): 2326-2337.
[7] Wood HM, Conway C, Daly C, et al.The clonal relationships between pre-cancer and cancer revealed by ultra-deep sequencing[J]. J Pathol, 2015, 237(3): 296-306.
[8] Hoefflin R, Lahrmann B, Warsow G, et al. Spatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity [J]. Nat Commun, 2016, 7: ncomms11845.
[9] Casasent AK, Schalck A, Gao R, et al. Multiclonal invasion in breast tumors identified by topographic single cell sequencing [J]. Cell, 2018, 172(1-2): 205-217.e212.
[10] Foschini MP, Morandi L, Leonardi E, et al.Genetic clonal mapping of in situ and invasive ductal carcinoma indicates the field cancerization phenomenon in the breast[J]. Hum Pathol, 2013, 44(7): 1310-1319.
[11] Heselmeyer-Haddad K, Berroa Garcia LY, Bradley A, et al.Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression[J]. Am J Pathol, 2012, 181(5): 1807-1822.
[12] Lourenco C, Kalkat M, Houlahan KE, et al. Modelling the MYC-driven normal-to-tumour switch in breast cancer [J]. Dis Model Mech, 2019, 12(7): dmm038083.
[13] Bao L, Qian Z, Lyng MB, et al.Coexisting genomic aberrations associated with lymph node metastasis in breast cancer[J]. J Clin Invest, 2018, 128(6): 2310-2324.
[14] Hernandez L, Wilkerson PM, Lambros MB, et al.Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection[J]. J Pathol, 2012, 227(1): 42-52.
[15] Ashworth A, Lord CJ, Reis-Filho JS.Genetic interactions in cancer progression and treatment[J]. Cell, 2011, 145(1): 30-38.
[16] Van Keymeulen A, Lee MY, Ousset M, et al.Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity[J]. Nature, 2015, 525(7567): 119-123.
[17] Haddad RI, Shin DM.Recent advances in head and neck cancer[J]. N Engl J Med, 2008, 359(11): 1143-1154.
[18] Teixeira VH, Pipinikas CP, Pennycuick A, et al.Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions[J]. Nat Med, 2019, 25(3): 517-525.
[19] Wangsa D, Quintanilla I, Torabi K, et al.Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness[J]. FASEB J, 2018, 32(7): 3502-3517.
[20] Lloyd MC, Cunningham JJ, Bui MM, et al.Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces[J]. Cancer Res, 2016, 76(11): 3136-3144.
[21] Sun R, Hu Z, Sottoriva A, et al.Between-region genetic divergence reflects the mode and tempo of tumor evolution[J]. Nat Genet, 2017, 49(7): 1015-1024.
[22] Waclaw B, Bozic I, Pittman ME, et al.A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity[J]. Nature, 2015, 525(7568): 261-264.
[23] Ryser MD, Min BH, Siegmund KD, et al.Spatial mutation patterns as markers of early colorectal tumor cell mobility[J]. Proc Natl Acad Sci USA, 2018, 115(22): 5774-5779.
[24] Zhang C, Zhang J, Xu FP, et al.Genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma[J]. J Thorac Oncol, 2019, 14(11): 1912-1923.
[25] Shahjehan F, Kamatham S, Kasi PM.Role of circulating tumor DNA in gastrointestinal cancers: update from abstracts and sessions at ASCO 2018[J]. Front Oncol, 2019, 9: 358-371.
[26] Orlando PA, Gatenby RA, Brown JS.Tumor evolution in space: the effects of competition colonization tradeoffs on tumor invasion dynamics[J]. Front Oncol, 2013, 3: 45-57.
[27] Liu S, Yang Z, Li G, et al.Multi-omics analysis of primary cell culture models reveals genetic and epigenetic basis of intratumoral phenotypic diversity[J]. Genomics Proteomics Bioinformatics, 2019, 17(6): 576-589.
[28] Fan J, Lee HO, Lee S, et al.Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data[J]. Genome Res, 2018, 28(8): 1217-1227.
[29] Darmanis S, Sloan SA, Croote D, et al.Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma[J]. Cell Rep, 2017, 21(5): 1399-1410.
[30] Martelotto LG, Baslan T, Kendall J, et al.Whole-genome single-cell copy number profiling from formalin-fixed paraffin-embedded samples[J]. Nat Med, 2017, 23(3): 376-385.
[31] Rye IH, Lundin P, Månér S, et al.Quantitative multigene FISH on breast carcinomas identifies der(1;16)(q10;p10) as an early event in luminal A tumors[J]. Genes Chromosomes Cancer, 2015, 54(4): 235-248.
[32] Konen J, Summerbell E, Dwivedi B, et al.Image-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion[J]. Nat Commun, 2017, 8: 15078.
[33] Zoeller EL, Pedro B, Konen J, et al. Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes [J]. J Cell Sci, 2019, 132(19): jcs231514.
[34] Martín-Pardillos A, Valls Chiva á, Bande Vargas G, et al.The role of clonal communication and heterogeneity in breast cancer[J]. BMC Cancer, 2019, 19: 666-693.
[35] Vinci M, Burford A, Molinari V, et al.Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells[J]. Nat Med, 2018, 24(8): 1204-1215.
[36] Marusyk A, Tabassum DP, Altrock PM, et al.Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity[J]. Nature, 2014, 514(7520): 54-58.