背景:抗有丝分裂一直是抗癌治疗的关键策略,针对癌细胞的基本特性,由于过度活跃的有丝分裂分裂,它们的不可控增殖。为了改善抗癌治疗,重要的是要发现癌细胞是否可以独立于有丝分裂而增殖并对抗有丝分裂剂产生抗性。
结果:在这项研究中,活细胞成像应用于两种肿瘤细胞的原代培养,和永生化的癌细胞系,检测异常增殖。从各种恶性肿瘤中分离的细胞,如III级血管外皮细胞瘤,非典型脑膜瘤,和转移性脑肿瘤表现出不同的细胞行为,包括变形虫隔离,尾矿,隧道,核酸DNA泄漏,以及类似原核生物的分裂,如二元裂变和萌芽脱落,在这项研究中,它们被统称为“非有丝分裂增殖”。相比之下,良性肿瘤包括I级血管外皮细胞瘤和脑膜瘤在此类行为上不明显。此外,当在不含任何抗癌药物的培养基中培养时,经过术前辅助化疗的复发性III级血管外皮细胞瘤的细胞逐渐从非有丝分裂增殖转变为子体数量变异(DNV)和有丝分裂的异常有丝分裂,最终有规律的有丝分裂。同样,当用抗癌药物表柔比星或顺铂治疗时,癌细胞系HeLa和A549显示出从常规有丝分裂到异常有丝分裂的转变,随着药物浓度的增加,非有丝分裂进一步成为主要的增殖模式。取出药物后,细胞逆转回到正常的有丝分裂,只有轻微的异常有丝分裂发生,伴随着干细胞标志物ALDH1,Sox,Oct4和Nanog。
结论:本研究表明,各种类型的恶性肿瘤,但不是良性的,癌细胞表现出指示非有丝分裂增殖的细胞行为,如二元裂变,这是典型的原核细胞分裂,暗示细胞水平的返祖现象。此外,通过三种增殖模式的可逆转变,即,有丝分裂,异常有丝分裂和非有丝分裂,当抗癌药物浓度显著增加诱导非有丝分裂或减少有利于有丝分裂时,观察到。非有丝分裂增殖在肿瘤耐药和复发中的潜在临床意义,其与肿瘤干细胞的关系值得进一步研究。
BACKGROUND: Anti-mitosis has been a key strategy of anti-cancer therapies, targeting at a fundamental property of cancer cells, their non-controllable proliferation due to overactive mitotic divisions. For improved anti-cancer therapies, it is important to find out whether cancer cells can proliferate independent of mitosis and become resistant to anti-mitotic agents.
RESULTS: In this study, live-cell imaging was applied to both primary-cultures of tumor cells, and immortalized cancer cell lines, to detect aberrant proliferations. Cells isolated from various malignant tumors, such as Grade-III hemangiopericytoma, atypical meningioma, and metastatic brain tumor exhibit distinct cellular behaviors, including amoeboid sequestration, tailing, tunneling, nucleic DNA leakage, as well as prokaryote-like division such as binary fission and budding-shedding, which are collectively referred to and reported as \'non-mitotic proliferation\' in this study. In contrast, benign tumors including Grade-I hemangiopericytoma and meningioma were not obvious in such behaviors. Moreover, when cultured in medium free of any anti-cancer drugs, cells from a recurrent Grade-III hemangiopericytoma that had been subjected to pre-operation adjuvant chemotherapy gradually shifted from non-mitotic proliferation to abnormal mitosis in the form of daughter number variation (DNV) and
endomitosis, and eventually regular mitosis. Similarly, when treated with the anti-cancer drugs Epirubicin or Cisplatin, the cancer cell lines HeLa and A549 showed a shift from regular mitosis to abnormal mitosis, and further to non-mitosis as the dominant mode of proliferation with increasing drug concentrations. Upon removal of the drugs, the cells reversed back to regular mitosis with only minor occurrences of abnormal mitosis, accompanied by increased expression of the stem cell markers ALDH1, Sox, Oct4 and Nanog.
CONCLUSIONS: The present study revealed that various types of malignant, but not benign, cancer cells exhibited cellular behaviors indicative of non-mitotic proliferation such as binary fission, which was typical of prokaryotic cell division, suggesting cell level atavism. Moreover, reversible transitions through the three modes of proliferation, i.e., mitosis, abnormal mitosis and non-mitosis, were observed when anticancer drug concentrations were grossly increased inducing non-mitosis or decreased favoring mitosis. Potential clinical significance of non-mitotic proliferation in cancer drug resistance and recurrence, and its relationship with cancer stem cells are worthy of further studies.