Department of Biochemistry, Faculty of Science, Jamia Hamdard, New Delhi, India.
PLoS One. 2012;7(11):e51125. doi: 10.1371/journal.pone.0051125. Epub 2012 Nov 30.
Human chorionic gonadotropin (hCG) was initially thought to be made only during pregnancy, but is now known to also be synthesized by a variety of cancers and is associated with poor patient prognosis. Transgenic expression of βhCG in mice causes hyper-luteinized ovaries, a loss in estrous cyclicity and infertility, increased body weight, prolactinomas and mammary gland tumors. Strategies were devised to generate antibody responses against hCG to investigate whether reversal of the molecular processes driving tumorigenesis would follow. hCG-immunized transgenic mice did not exhibit increases in body weight or serum prolactin levels, and gross ovarian and pituitary morphology remained normal. While non-immunized transgenic animals demonstrated heightened levels of transcripts associated with pituitary tumorigenesis (HMG2A, E2F1, CCND1, PRL, GH, GAL, PTTG1, BMP4) and decreased levels of CDK inhibitors CDKN1B (p27), CDKN2A (p16) and CDKN2c (p18), immunization led to a reversal to levels found in non-transgenic animals. Serum derived from transgenic (but not non-transgenic) mice led to enhanced transcription as well as expression of VEGF, IL-8, KC (murine IL-8) and MMP-9 in tumor cells, effects not seen when sera derived from hCG-immunized transgenic mice was employed. As the definitive indication of the restoration of the reproductive axis, immunization led to the resumption of estrous cyclicity as well as fertility in transgenic mice. These results indicate that hCG may influence cancer pathogenesis and progression via several distinct mechanisms. Using a stringent in vivo system in which βhCG acts both a "self" antigen and a tumor-promoting moiety (putatively akin to the situation in humans), the data builds a case for anti-gonadotropin vaccination strategies in the treatment of gonadotropin-dependent or secreting malignancies that frequently acquire resistance to conventional therapy.
人绒毛膜促性腺激素（hCG）最初被认为仅在怀孕期间产生，但现在已知也由多种癌症合成，并与患者预后不良相关。βhCG 在小鼠中的转基因表达导致黄体化过度的卵巢、发情周期丧失和不孕、体重增加、催乳素瘤和乳腺肿瘤。设计了各种策略来产生针对 hCG 的抗体反应，以研究是否会逆转驱动肿瘤发生的分子过程。hCG 免疫的转基因小鼠没有表现出体重增加或血清催乳素水平升高，并且卵巢和垂体的大体形态仍然正常。虽然未免疫的转基因动物表现出与垂体肿瘤发生相关的转录本水平升高（HMG2A、E2F1、CCND1、PRL、GH、GAL、PTTG1、BMP4）和 CDK 抑制剂 CDKN1B（p27）、CDKN2A（p16）和 CDKN2c（p18）水平降低，但免疫导致逆转至非转基因动物中发现的水平。来自转基因（而非非转基因）小鼠的血清导致肿瘤细胞中的 VEGF、IL-8、KC（鼠 IL-8）和 MMP-9 的转录和表达增强，而当使用来自 hCG 免疫的转基因小鼠的血清时则未观察到这些作用。作为生殖轴恢复的明确指征，免疫导致转基因小鼠恢复发情周期和生育能力。这些结果表明，hCG 可能通过几种不同的机制影响癌症的发病机制和进展。使用严格的体内系统，其中βhCG 既作为“自身”抗原又作为促进肿瘤的部分（推测类似于人类的情况），数据为促性腺激素依赖性或分泌性恶性肿瘤的抗促性腺激素疫苗策略提供了依据，这些恶性肿瘤经常对常规治疗产生耐药性。
