为什么有些前列腺癌治疗后复发？
Why Some Prostate Cancers Recur After Treatment为什么有些前列腺癌治疗后复发？
http://www.medicalnewstoday.com/articles/85383.php
Cancer researchers have long worked to understand why some prostate cancers recur after the use of therapies designed to stop the production of testosterone and other androgens that fuel cancer cell growth. New research has now detected that androgen-synthesizing proteins are present within cancer cells, which suggests that cancer cells may develop the capacity to produce their own androgens.
癌症研究者长期以来致力于研究为什么有些前列腺癌在采取了阻断具有促进癌细胞生长作用的睾酮以及其他雄激素的产生后仍然会有肿瘤复发。新近研究发现癌细胞内存在雄激素合成蛋白，这表明，癌细胞具备产生自身所需雄激素的能力。
The presence of these proteins may explain why some prostate cancers become resistant to these widely-used therapies, and offers new directions for research into future treatments that could block the development of androgens in the cancer cells. The study, funded by the Prostate Cancer Foundation and the National Cancer Institute, was presented today at the Foundation's annual Scientific Retreat.
这些蛋白的存在可以解释为什么有些前列腺癌会对这一广泛适用的治疗方案产生抵抗性，并且为今后研究阻断癌细胞内产生雄激素的治疗措施提供了新的方向。这项研究由前列腺癌基金和国家癌症研究所资助，现今在年度科研基金会上提出来。
Androgen-deprivation therapy is routinely used in the treatment of advanced (metastatic) prostate cancer, in order to deprive cancer cells of these hormones that fuel their growth. However, over time cancer cells can become \"androgen independent,\" and grow even in the presence of these medications. This type of the cancer is a lethal form of the disease, with most patients dying 18 to 24 months after becoming resistant to hormone suppression. Research in the field has focused on understanding the mechanisms used by these cancer cells to become \"castration resistant\".
雄激素阻断疗法常规用于治疗晚期（转移性）前列腺癌，目的是去除供应癌细胞生长的激素。但是，经过一段时间癌细胞可以变为雄激素非依赖性，即使在维持这种治疗情况下肿瘤仍然继续生长。这类肿瘤是该疾病的致命类型，多数病人在对激素抑制产生抗性后18-24个月死亡。这一领域的研究一直集中于探讨癌细胞转变为对去势具有抵抗性的内在机制。
Investigators Peter Nelson, M.D., Elahe Mostaghel, M.D., Ph.D., and Bruce Montgomery, M.D. from the Fred Hutchinson Cancer Research Center and University of Washington, conducted tests on tumors removed and preserved from deceased prostate cancer patients during \"rapid autopsies\" immediately after death. All the patients had received androgen-blocking therapies during the course of treatment to suppress tumor growth.
Fred Hutchinson癌症研究中心和华盛顿大学的Peter Nelson博士、Elahe Mostaghel博士、以及Bruce Montgomery博士对切除的肿瘤和前列腺癌死亡患者死后立即进行快速尸检的肿瘤进行了研究。所有病人都在治疗期间接受了雄激素阻断治疗以抑制肿瘤的生长。
The researchers were able to detect in the tumors the key proteins, or enzymes, needed for a cell to produce its own testosterone from cholesterol present in the cell. \"This study, along with other research in the field, suggests that cancer cells may have the ability to adapt and produce their own androgens that permit these cancer cells to survive,\" explained Nelson. \"While this study does not prove that the cancer cells act in this way, it does show it is possible.\"
研究者们在肿瘤中能够检测到细胞内用于将胆固醇合成自身睾酮的关键蛋白、或酶。“这一研究以及该领域的其他研究表明，癌细胞具备适应和产生自身雄激素以维持细胞存活的能力，” Nelson解释道，“虽然这项研究没有证明癌细胞是通过这种方式起作用，但却表明了这种可能性。”
The work of Nelson and Montgomery was inspired, they say, by the work of Jack Geller in the 1980's, which demonstrated that testosterone and potent metabolites could still be found in prostate tumors at levels exceeding those found in the blood, which suggested the cancer could develop its own testosterone. Recent research by Jim Mohler, M.D., Stephanie Page, M.D., Ph.D., and other investigators has also revisited these ideas. \"In other studies, men without prostate cancer who received androgen-suppressing drugs also showed surprisingly high levels of androgen in their prostates even with low levels in their blood,\" noted Nelson, \"and biopsies of the prostate following testosterone suppression in men who have prostate cancer have shown similar results.\"
Nelson和Montgomery说，他们的工作受启发于Jack Geller早在1980年所做的工作，该研究发现睾酮及其高效的代谢物在前列腺肿瘤中的浓度仍然明显高于血液中浓度，表明肿瘤能够产生自己的睾酮。近期Jim Mohler博士、Stephanie Page博士以及其他研究者也回顾了这些思路。“在其他研究中，未患前列腺癌的病人接受雄激素抑制药物后，其前列腺内雄激素浓度明显增高，尽管在血液中的浓度较低，” Nelson解释道，“前列腺癌患者在接受睾酮抑制治疗后前列腺的活检也有类似的发现。”
The research by the Hutchinson Center/University of Washington team now offers a plausible explanation and mechanism of action for these findings. In the study, researchers removed entire metastases, or tumors, from deceased prostate cancer patients who had agreed to be part of a \"rapid autopsy\" research program. At least three tumors were removed from each patient, and examined for androgen levels and the presence of the enzymes responsible for androgen metabolism.
华盛顿大学Hutchinson中心团队的研究对这些现象的机制做出了可能的解释。在该研究中，研究者征得前列腺癌患者同意后，在死后进行快速尸检，切除整个转移灶或肿瘤，每个病人至少取出了3个肿瘤，研究雄激素的水平以及参与雄激素代谢的酶。
Nelson noted that the study offers directions for future research in this area. \"The next phase will be to determine the source of androgen precursors. These are likely to be derived from andrenal androgens, or possibly from cholesterol. A key experiment will be to follow these precursor molecules in the cancer cells to see if they are converted to testosterone,\" said Nelson, \"hence proving these tumor cells are actually capable of such a conversion.\"
Nelson认为该研究为这一领域的深入研究提供了方向。“下一步将是明确雄激素的来源，这些激素似乎来源于肾上腺分泌的雄激素，或者来源于胆固醇。接下来将进行一项关键性实验，追踪癌细胞中的这些前体分子，研究它们是否会转变为睾酮，” Nelson说，“这样就可以证明这些肿瘤细胞确实具备这种转换能力。”
New medications are being tested in the early stages of clinical trials with the goals of blocking androgen synthesis. Abiraterone, for example, seeks to inhibit the enzymes in the metabolic pathways that convert cholesterol to androgens, and work by blocking androgen synthesis in both the adrenal gland and possibly in the tumors themselves. Other classes of drugs being tested attempt to more completely block interactions with the receptor for androgens within the tumor cells, or alter the degradation of androgens. Rather than continuous treatment which is associated with side-effects, a strategy of maximally inhibiting the androgen axis for a short-time or on an intermittent basis could have the effect of destroying or suppressing cancer cell growth for long time periods. Investigators leading these trials also discussed initial findings in the session at PCF's annual Scientific Retreat.
目前正在进行旨在阻断雄激素合成的新药早期临床试验。例如阿比特龙（Abiraterone）就能抑制胆固醇转变成雄激素代谢通路中的酶，在肾上腺，甚至在肿瘤本身能够阻断雄激素的合成。正在研究的其他种类药物，希望能够更完全地阻断激素与肿瘤细胞内雄激素受体之间的相互作用，或者改变雄激素的降解。与具有副作用的持续性治疗不同，短期内最大程度地阻断雄激素轴或者间断阻断可能达到更持久地破坏或抑制癌细胞生长的作用。主导这些实验的研究者也在PCF年度学术会上讨论了初步的结果。
Nelson lauded the Prostate Cancer Foundation for their leadership role in funding research in the field. \"What PCF has allowed is exploration of innovative and high risk ideas, instrumental in allowing us to pursue this area of investigation,\" emphasized Nelson.
Nelson赞扬了前列腺癌基金会在资助这一领域研究中的领军作用，“PCF资助创新性和高风险的思路，帮助我们继续进行该领域的研究，” Nelson强调。
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