臨床研究責任者:遠藤陽一表参道ヨーイークリニック 院長
2022年6月17日:前立腺針生検検体計10本 検体1から5、10は、GS※ 4+4=8。検体7.8は、GS4+3=7
【病理診断】Needle biopsy of prostate Adenocarcinoma 60代男性:前立腺がん 被膜外浸潤、リンパ節転移 肥大した前立腺は5㎝
【2022年5月26日】:PSA:151.792 【2022年6月29日】:PSA188.004

June 17, 2022: 10 prostate needle biopsy specimens Samples 1 to 5 and 10 are GS* 4 + 4 = 8. Specimen 7.8 is GS4 + 3 = 7 Male in his 60s: Prostate cancer, extracapsular invasion, lymph node metastasis Enlarged prostate is 5 cm [May 26, 2022] 😛 SA: 151.792 [June 29, 2022] 😛 SA188.004

mRNA-ecmRV-encordingP53/PTEN/Cdc6knock down shRNA/p16/ INJEX & Intravenous Injection treatment


Treatment continues of March 2024


July 22, 2022 (First-choice hormone therapy shows enlarged lymph nodes in both PSA and elevated imaging)

September 22, 2022 (portrait of the deceased before the start of GENE Therapy treatment)


2024年1月24日 CT検査

No abdominal lymph node enlargement is observed. No bladder wall thickening findings The prostate gland is enlarged, but it is difficult to evaluate the tumor with CT Bladder invasion findings are also not identifiable by CT Prostate enlargement is about 3 cm

増加する前立腺がんProstate cancer on the rise


The National Cancer Center publishes statistical information as a nationwide estimate. According to this statistic, in 1975, there were 2,412 people, but it gradually increased, exceeding 10,000 in 1993 and 50,000 in 2008. Since then, the number of cases has been increasing, and from 2011 to 2015, the number of affected people has been 70,000~80,000 every year. The upward trend is expected to continue, exceeding 100,000 in 2020.
The reason for this rapid increase in prostate cancer compared to the past is thought to be an increase in the number of high-risk people due to the aging of Japan men and changes in dietary habits, and an increase in the detection rate due to the spread of PSA testing.





  • 前立腺がんの末期症状として、前立腺の中を通っている尿道が詰まってしまい、排尿できないような状態になってしまうことがあります。また、骨転移に関連した症状が多く発生します。特に、前立腺の近くにある腰椎や骨盤に転移しやすく、骨転移による強い腰の痛みや、下半身の麻痺が生じることもあります。また、骨以外にもリンパ節や肝臓、肺、脳などへの転移を起こすこともあり、転移したそれぞれの臓器の機能の低下や障害という形で症状が生じます。
  • 末期の前立腺がんでは、がんを完全に取り除くことが難しくなります。そのため、体や心のつらさを緩和するための治療(緩和ケア)に比重を移していきます。これまでは、がんの経過が進むまでは「がん本体」に対する治療を行い、治療終了後に体や心のつらさに対する緩和ケアを行うという考え方でした。しかし、前立腺がんの初期であっても体や心のつらさはあります。
  • そのため、最近の考え方では、緩和ケアは、がんの早い時期にも生活を守り、自分らしい暮らしを保つために必要なこととして捉えられています。つまり、緩和ケアは末期にだけ行う治療というわけではなく、がんの早期から生活の質を守るための治療・対策として行われています。
  • こうした緩和ケアは、担当医・看護師・麻酔科医・薬剤師・ソーシャルワーカーなどの緩和ケアチームが協力して、個々人の状況を踏まえて治療やアドバイスを行います。適切な緩和ケアの実施のためには、患者さん本人から痛みやつらい事柄を伝えることが必要になります。つらいことは、我慢しないで、自分の言葉で伝えることが重要です。
  • 特に、前立腺がんは他の多くのがんとは異なり、ステージIVであっても高い生存率が期待できます。そのため、末期の症状による様々な体や心のつらさを取り除くための緩和ケアは大変重要です。前立腺がんと共に生きる人生を有意義なものにするためにも、積極的な緩和ケアの利用が必要となります。

Changes in the number of deaths
The National Cancer Center also publishes statistical information on the number of deaths. Since 2009, more than 10,000 people have died each year. Back in 1975, the number of deaths was 1,267, and since then it has increased as well as the number of cases. However, the increase is smaller than the number of affected people, and the statistics show that the survival rate is increasing with treatment.
End-stage prostate cancer and care
End-stage symptoms of prostate cancer
One of the terminal symptoms of prostate cancer is that the urethra, which runs through the prostate, may become blocked, making it impossible to urinate. In addition, there are many symptoms associated with bone metastases. In particular, it is easy to metastasize to the lumbar spine and pelvis, which are located near the prostate, and severe lower back pain due to bone metastasis and paralysis of the lower body may occur. In addition to the bones, it can also spread to lymph nodes, liver, lungs, brain, etc., and symptoms occur in the form of a decrease or impairment in the function of each metastatic organ. About palliative care
With end-stage prostate cancer, it is difficult to completely get rid of the cancer. Therefore, we will shift the emphasis to treatment (palliative care) to alleviate physical and mental pain. Until now, the idea was to provide treatment for the “main cancer” until the cancer progressed, and then provide palliative care for physical and mental pain after the treatment was completed. However, even in the early stages of prostate cancer, there are physical and mental pains. Therefore, in recent thinking, palliative care is seen as a necessary part of protecting one’s life and maintaining one’s own life even in the early stages of cancer. In other words, palliative care is not only a treatment that is performed at the end of life, but is also used as a treatment and measure to protect the quality of life from the early stages of cancer.
In palliative care, palliative care teams such as doctors, nurses, anesthesiologists, pharmacists, and social workers work together to provide treatment and advice based on each individual’s situation. In order to provide appropriate palliative care, it is necessary for the patient to communicate their pain and painful matters. It is important not to put up with painful things and to communicate them in your own words.
In particular, prostate cancer, unlike many other cancers, has a high survival rate, even in stage IV. Therefore, palliative care is very important to relieve various physical and mental pains caused by terminal symptoms. In order to make life with prostate cancer meaningful, active palliative care needs to be used.








例えば「T2N0 M0」なら、 「がんは前立腺に限局しており、リンパ節転移も遠隔転移もない」という意味です。


PSA(前立腺特異抗原)は、前立腺の細胞でつくられるタンパク分解酵素です。前立腺に何か異常があると、これが血中に漏れて、血清中PSA値が上昇します。前立腺肥大症や前立腺炎でも値が上昇するため、高値だからといって必ずしも前立腺がんとは限らないので、がんの疑いがある、と考えればよいでしょう。PSA値が基準値上限を超えた場合、最終的にがんと診断される率は40~50%で、値が高いほど、前立腺がんが強く疑われます。また、治療後に再発・転移の有無をチェックするときにも、まずこの検査が用いられます。 PSA (prostate-specific antigen) is a proteolytic enzyme produced by cells in the prostate gland. If there is something wrong with the prostate, it will leak into the blood and increase the serum PSA level. Benign prostatic hyperplasia and prostatitis also increase the value, so just because it is high does not necessarily mean that it is prostate cancer, so it is safe to assume that cancer is suspected. If the PSA level exceeds the upper limit of the reference value, the rate of final cancer diagnosis is 40~50%, and the higher the value, the stronger the suspicion of prostate cancer. This test is also used first to check for recurrence or metastasis after treatment. 10ng/mLを超える場合、がんである確率は50~80%です
If it exceeds 10 ng/mL, the probability of cancer is 50~80%



Gleason Score

Cancer cells are divided into five types according to their malignancy and arranged in order of low malignancy. Look at the characteristics of the cancer found in the tissue taken from the biopsy and add the number of the most common type and the second most common type.


  • 前立腺がんの根治的治療(がんを治す治療)には手術と放射線治療があります。放射線治療の効果は、手術と同等だと考えられているので、基本的にはどちらでも選ぶことができます。放射線治療は、骨などに転移して痛みやしびれなどを起こしている人の症状を緩和する目的でも行われます。
  • 前立腺がんの放射線治療にはいくつか種類があります。


  • 外照射
  • 内照射:小線源療法(組織内照射)
  • トリモダリティ(外照射と内照射、ホルモン治療の併用)
  • 陽子線治療
  • 重粒子線治療
  • それぞれの特徴について個別に説明します。


  • 外照射は放射線を身体の外から当てる治療の方法を指します。外来治療として行われることが多いです。1回あたりの治療時間は20分程度で、36回から40回の通院が必要です。
  • 放射線治療で用いる放射線の量をGy(グレイ)という単位で表します。
  • 前立腺がんの放射線治療は72-80Gyの照射線量が必要です。一度に照射すると正常組織への影響が強くなってしまうので、1回の照射線量は2Gy程度に分散させることが多く、そのため36回から40回の通院が必要になります。休日を考慮すると治療を完了するまでに2か月程度を要します。 また、前立腺がんの悪性度が高くないタイプでは、一回に照射する放射線の量を増加させて短期間で治療を終える方法(寡分割照射・超寡分割照射)もあります 行えるかどうかは医療機関ごとで異なるので、興味がある人は治療を検討している医療機関で確認してみてください。


  • 頻尿
  • 排尿時痛
  • 下痢
  • 血便(直腸出血)
  • 勃起不全


強度変調放射線治療 (IMRT:アイエムアールティー)について






内照射を行う条件は施設により異なっていますが、低リスクの前立腺がんの人に対して行う施設が多いです。低リスクの前立腺がんに対する治療効果は、内照射と手術とで同等と考えられています。 中間リスク・高リスクの人には内照射に外照射を加えた方法や、さらにホルモン治療を加えた方法(トリモダリティ治療)が必要になります。トリモダリティ治療については後述します。 リスク分類で内照射の条件に当てはまったとしても、前立腺が極端に大きい人には内照射による治療ができないことがあるので注意が必要です。

  • 直腸出血
  • 勃起機能の低下
  • 頻尿
  • 排尿時痛
  • 尿意切迫感
  • 排尿困難









・効果が高くなるとはいえ、放射線治療を行う全ての人にホルモン治療が必要ではありません。ホルモン治療には副作用もあるので、必要のない人には行わないほうが良いです。具体的には、低リスクの前立腺がんに放射線治療を行う場合は、ホルモン治療の必要はありません。 放射線治療に合わせて行われるホルモン治療は、放射線治療が始まる6ヶ月前から開始され、放射線治療が終わった後もしばらく継続されます。
・前立腺がんの腫瘍マーカーであるPSAを上手に使うと、再発を早期に発見することができます。他のがんでは、CT検査などの画像検査で転移を確認した時を再発とすることが多いのですが、前立腺がんでは画像検査で見つかる前にPSAの値の上昇から再発を発見できます。 PSAの上昇によって定義される再発を生化学的再発と呼びます。具体的には、放射線治療で根治的治療を行なった場合、PSAが治療後一番低かった数値から2.0ng/mL上昇した時点で再発とします。再発の定義は手術を行った場合やホルモン療法とは異なります。この点には注意が必要です。


  • ホルモン療法は次のような人に行われます。
  • 転移がある人
  • 高齢者
  • 手術や放射線治療後に再発する可能性が高い人







前立腺がんには、精巣や副腎から分泌されるアンドロゲン(男性ホルモン)の刺激で病気が進行する性質があります。内分泌療法は、アンドロゲンの分泌や働きを妨げる薬によって前立腺がんの勢いを抑える治療です。内分泌療法は手術や放射線治療を行うことが難しい場合や、放射線治療の前あるいは後、がんがほかの臓器に転移した場合などに行われます。 ホルモン療法は非常に有効な治療法ですが、アンドロゲンが押さえられることで、骨密度が低下します。骨密度が低下すると骨折や腰痛等の症状が起き、生活の質が低下します。 ホルモン療法を開始された患者様に対して、早期から骨密度の評価を行い、骨粗鬆症対策を行っています。主な治療法は年一回、リクラストなどの骨粗鬆症の予防薬を点滴投与します。歯の副作用が出ることがあるため、投与前と投与後も定期的に歯科受診をしてもらいます。


The Pathogenesis of Prostate Cancer


Prostate cancer is a major cause of pathology in men world-wide and is age-related. Rare in the under 40s, a third of all those over 80 have been shown to have prostate lesions at autopsy. Both hereditary and molecular influences appear to be involved in the pathogenesis of the condition. Androgenic receptors play a major role in most, but not all, prostate cancers. The cell type involved is related to the aggressiveness of the malignancy. Of those that develop the disease, some die with prostate cancer, others because of it. Over 90% of the cancers are adenocarcinomas. The likelihood of progression of the disease can, but only to a degree, be predicted on histological examination, according to the Gleason Scale and its modifications. These assess degrees of tissue differentiation. Use of blood levels of prostate specific antigen levels as an indication of the activity of tumors is also not straightforward. Our understanding of the disease mechanisms needs further expansion if we are to advance diagnosis of aggressive tumors and develop more effective therapies.



It is a heterogenous disease, with a wide scope of disease pathogenesis from asymptomatic and prolonged, where men die with the disease, to severe malignancy where men die from it or have significant morbidity. At the turn of the century, a Spanish study evaluating prostate histology at autopsy identified that men from the third decade onwards have neoplastic lesions of the prostate and 33% of the male population in their eighth decade have prostate cancer (2). In addition, prostate cancer is the most commonly diagnosed malignancy in older men (over the age of 65) worldwide, especially in highly developed countries (Australia, New Zealand, Northern and Western Europe, and North America) (3–5). The high prevalence of the disease can be attributed to the volume of cases identified through prostate specific antigen (PSA) testing, especially in the United States (6). However, prostate cancer screening has been surrounded by controversy and can be seen as an ethical dilemma. Studies have shown that distinguishing between indolent pathology and aggressive tumors using PSA levels alone is insufficient as it is not cancer-specific (7). It is also a challenge as high PSA levels do not directly correlate with pathogenicity and requires further investigations through multiparametric magnetic resonance imaging (MRI) and histology. Therefore, early diagnosis often leads to harm to patients via overdiagnosis and unnecessary treatment (radical surgery, radiotherapy and chemical castration) leading to reduced quality of life (QoL) and psychological trauma knowing they have a cancer diagnosis (7). This chapter aims to address the developmental processes involved in prostate cancer including hereditary and molecular components.


ARs are essential transcription factors in the regulation of male sexual development and accessory sexual organ maintenance (27). Prostate cancer growth and disease progression is initially dependent on AR activation, via testosterone and dihydrotestosterone (DHT), leading to nuclear translocation of the receptor and subsequent binding to androgen response elements (AREs) initiating transcription of genes that regulate cellular differentiation, proliferation and apoptosis (28) (Figure 2). Therefore, AR stimulation is integral to the maintenance and survival of prostate luminal epithelial cells. The hypothalamic-pituitary-gonadal (HPG) axis regulates the production of androgens. Androgens are primarily produced in Leydig cells of the testes under the regulation of luteinizing hormone (LH) secreted by the anterior pituitary gland, which in turn is regulated by gonadotropin-releasing hormone (GnRH). Testosterone is converted into DHT in the epithelial cells of the prostate by 5α-reductase which acts as a potent ligand to cytoplasmic ARs.



Androgenic regulation of prostate cancer. In the cytoplasm, activity of ARs is regulated by ligand-binding and heat shock proteins (HSP). Testosterone (T) is transported into the cytoplasm of androgen-receptive cells and is converted to DHT by 5-α


AR-independent pathways include alternative peptide growth factors including transforming growth factor-β (TGF-β), epidermal growth factor (EGF), fibroblast growth factor (FGF) and insulin-like growth factor (IGF) (41, 42). These peptide factors help facilitate the AR-regulated proliferation of prostate epithelial cells via a process called ‘cross-talk’ (42). For instance, EGF, alongside its membrane-associated tyrosine receptor kinase EGF-1 (EGFR, HER1), is involved in the motility and invasiveness of cancer cells through enhanced migration through extracellular matrix barriers, basal membranes and then the subsequent cellular proliferation (43). ErbB2 (HER2), a member of the EGFR family, is upregulated in CRPC and has been associated with androgen-independent transcriptional activation of ARs and the subsequent heightened expression of PSA (29). HER2/neu receptors, part of the EGFR family, are found overexpressed in breast and ovarian cancers. They have been proposed as a mechanism for AR-independent activation in CRPC (44). In vitro and in vivo studies involving forced overexpression of HER2/neu receptors or transfection of HER2/neu in prostate cancer cell lines (LNCaP) identified promotion to AR-independence and expression of PSA (44, 45).
AR非依存経路には、トランスフォーミング成長因子-β(TGF-β)、上皮成長因子(EGF)、線維芽細胞増殖因子(FGF)、インスリン様成長因子(IGF)などの代替ペプチド成長因子が含まれる(41,42)。 これらのペプチド因子は、「クロストーク」と呼ばれるプロセスを介して、AR制御された前立腺上皮細胞の増殖を促進するのを助ける(42)。例えば、EGFは、膜結合型チロシン受容体キナーゼEGF-1(EGFR、HER1)とともに、細胞外マトリックスバリア、基底膜、そしてその後の細胞増殖を介した遊走の増強を通じて、がん細胞の運動性と浸潤性に関与している(43)。EGFRファミリーのメンバーであるErbB2(HER2)はCRPCでアップレギュレーションされ、アンドロゲン非依存性のARの転写活性化とそれに続くPSAの発現亢進と関連している(29)。EGFRファミリーの一部であるHER2/neu受容体は、乳がんおよび卵巣がんにおいて過剰発現していることがわかっています。それらはCRPCにおけるAR非依存的な活性化のメカニズムとして提案されている(44)。前立腺がん細胞株(LNCaP)におけるHER2/neu受容体の強制過剰発現またはHER2/neuのトランスフェクションを含むin vitroおよびin vivo試験により、AR非依存性への促進とPSAの発現が確認されました


The reduction in AR activation leads to hypersensitization of other pathways. For instance, the upregulation in IGF-1, EGF and other growth factors subsequently activate ErbB2 and other tyrosine receptor kinases (32). This results in the activation of phosphatidylinositol 3-kinase (PI3K) and subsequent PI3K-AKT-mTOR pathway (46, 47). PI3K activation, converts phosphatidylinositol 4,5-bisphosphonate (PIP2) to phosphatidylinositol 3–5-triphosphate (PIP3) which recruits protein kinase B (AKT) proteins to the luminal cell cytoplasm (46). AKT signaling involves deregulating the tuberous sclerosis 1/2 (TSC1/2), an inhibitor of the GTP-binding protein RHEB, which in turn is responsible for the activation of the mechanistic target of rapamycin complex 1 (mTORC1), a kinase that is critical to the regulation of cell cycle. mTORC1 impedes autophagy and promoting prostate cancer cellular proliferation (Figure 3) (46). Through this pathway, studies have proven that IGF-1 can activate AR-mediated gene transcription and stimulate the production of PSA in LNCaP cells. As a result, the PI3K-AKT-mTOR pathway is of interest in establishing new therapeutic targets for patients with CRPC (47, 48).

AR活性化の減少は、他の経路の過敏化につながります。例えば、IGF-1、EGFおよび他の成長因子のアップレギュレーションは、その後、ErbB2および他のチロシン受容体キナーゼを活性化する(32)。この結果、ホスファチジルイノシトール3-キナーゼ(PI3K)とそれに続くPI3K-AKT-mTOR経路が活性化される(46,47)。 PI3Kの活性化は、ホスファチジルイノシトール4,5-ビスホスホネート(PIP2)をホスファチジルイノシトール3-5-三リン酸(PIP3)に変換し、プロテインキナーゼB(AKT)タンパク質を管腔細胞質にリクルートする(46)。AKTシグナル伝達は、GTP結合タンパク質RHEBの阻害剤である結節性硬化症1/2(TSC1/2)の脱制御に関与し、細胞周期の調節に重要なキナーゼであるラパマイシン複合体1(mTORC1)の機構的標的の活性化に関与しています。mTORC1はオートファジーを阻害し、前立腺がんの細胞増殖を促進する(図3)(46)。この経路を通じて、IGF-1がARを介した遺伝子転写を活性化し、LNCaP細胞におけるPSAの産生を刺激できることが研究で証明されています。その結果、PI3K-AKT-mTOR経路は、CRPC患者の新しい治療標的を確立する上で興味深いものです(47,48)。

Androgen receptor bypass pathways. Reduced AR suppression leads to the upregulation of Tyrosine Receptor Kinases (RTK) e.g., ErbB2 by factors such as IGF, GF and EGF. RTK activation leads to the stimulation of PI3K with phosphorylates PIP2 into PIP3. This process is inhibited by the tumor suppressor PTEN. PIP3 activates AKT which indirectly suppresses the activity of the cell survival protein mTORC1 by inhibiting TSC1/2 which in turn suppresses the GTP-binding protein RHEB. mTORC1 is pivotal in the translation of proteins and therefore protein synthesis. Therefore, AR inhibition, as well as PTEN suppression, leads to overactivation of the PIP3-AKT-mTOR pathway – creating an alternate route for cell survival in CRPC.



Genetic analysis of CRPC tumors has identified that the gene for the protein phosphatase and tensin homolog (PTEN) is mutated in 20% of cases (49). PTEN is a tumor suppressor gene, it acts by negatively regulating the PI3K-AKT-mTOR pathway and halting the cell-cycle at the G1 stage therefore halting cellular proliferation. Loss of PTEN thus results in an increase in the PI3K-AKT-mTOR pathway as well as impairing normal AR regulation, resulting in increased cellular proliferation, AR expression and reduced apoptosis (29). PTEN’s expression is inversely correlated with Gleason Score and therefore is associated significantly with aggressive prostate cancer (Gleason >7, P = 0.0004), with up to 20% of high-grade tumors being negative for PTEN expression (50).

CRPC腫瘍の遺伝子解析で、タンパク質ホスファターゼおよびテンシンホモログ(PTEN)の遺伝子が症例の20%で変異していることが同定れている(49)。PTENは腫瘍抑制遺伝子であり、PI3K-AKT-mTOR経路を負に制御し、細胞周期のG1期細胞増殖を止める。したがって、PTENの喪失はPI3K-AKT-mTOR経路の増加をもたらし、正常なAR調節を損ない、細胞増殖の増加、AR発現の増加、およびアポトーシスの減少をもたらす(29)。PTENの発現はグリーソンスコアと逆相関しており、それゆえ侵攻性前立腺がんと有意に関連しており(グリーソン>7、P = 0.0004)、高悪性度腫瘍の最大20%がPTEN発現陰性である(50)。


The tumor microenvironment (TME) describes the vast array of supporting cells (including immune cells, fibroblasts, adipose cells, microvasculature, and components of the extracellular matrix [ECM]) that form a complex network surrounding tumor cells that may play a role in their pathogenicity, especially involving their transition from normal cells to neoplastic cancer cells themselves (5152). Studies have reported that tumor cells are able to ‘hijack’ immune cells and prime them to aid metastatic potential (51). As studied by Chen et al. (53), immune cells can be infiltrated by tumor cells forming tumor-associated macrophages (TAMs). They identified that CD8-T cells can express PSA in aggressive forms of prostate cancer, and this perhaps enhances the tumor’s ability to metastasize to lymphatic tissue and bone. Therefore, the TME may provide the environment whereby alternative cell types transform into malignant tumor cells in aggressive prostate cancer and influence the ability to invade local and systemic structures (54).

腫瘍微小環境(TME)は、腫瘍細胞を取り巻く複雑なネットワークを形成する膨大な数の支持細胞(免疫細胞、線維芽細胞、脂肪細胞、微小血管系、細胞外マトリックス[ECM]の構成要素を含む)を記述し、腫瘍細胞の病原性に関与している可能性があり、特に正常細胞から腫瘍性癌細胞自体への移行に関与している(51,52) ).研究によると、腫瘍細胞は免疫細胞を「ハイジャック」し、転移の可能性を助けるために免疫細胞をプライミングすることができる(51)。Chenら(53)が研究したように、免疫細胞は、腫瘍関連マクロファージ(TAM)を形成する腫瘍細胞によって浸潤させることができる。その結果、CD8-T細胞が侵攻性の前立腺がんにおいてPSAを発現し、これが腫瘍のリンパ組織や骨への転移能力を高める可能性があることが明らかになった。したがって、TMEは、侵攻性前立腺癌において代替細胞型が悪性腫瘍細胞に形質転換し、局所的および全身的構造に浸潤する能力に影響を与える環境を提供するかもしれない(54)。


Dysregulation in the programmed cell death mechanisms (apoptosis) is important in the pathogenesis of prostate cancer and is deemed a key driver in the exponential growth of tumor cells (55). There are two distinct pathways, intrinsic and extrinsic, that are involved in the normal signaling of programmed cell death that are critical to tissue homeostasis. Extrinsic (receptor pathway) mechanisms involve the intracellular binding of apoptosis-inducing ligands, such as tumor necrosis factor (TNF), to cell-surface death receptors that are part of the TNF-R superfamily such as CD95 (Apo-1/Fas) or TNF-related apoptosis-inducing ligand (TRAIL) receptors. These receptors contain the Fas-associated death domain (FADD) and form death-inducing signaling complexes (DISCs) with intracellular caspases that contain a death-effector domain (DED) such as caspases 8 and 10 (56, 57). Effector caspases, including caspase-3, activate proteolysis and cleavage of intracellular/intranuclear substrates, inducing apoptosis (56).
プログラムされた細胞死機構の調節不全(アポトーシス)は前立腺癌の病因において重要であり、腫瘍細胞の指数関数的な増殖における重要な推進力であると考えられている(55)。内因性経路と外因性経路の2つの異なる経路があり、組織の恒常性維持に重要なプログラム細胞死の正常なシグナル伝達に関与しています。外因性(受容体経路)メカニズムには、腫瘍壊死因子(TNF)などのアポトーシス誘導リガンドの細胞内結合が関与し、CD95(Apo-1 / Fas)またはTNF関連アポトーシス誘導リガンド(TRAIL)受容体などのTNF-Rスーパーファミリーの一部である細胞表面死受容体に結合します。これらの受容体はFas関連デスドメイン(FADD)を含み、カスパーゼ8や10などのデスエフェクタードメイン(DED)を含む細胞内カスパーゼと死誘導シグナル複合体(DISC)を形成する(56,57)。 カスパーゼ-3を含むエフェクターカスパーゼは、細胞内/核内基質のタンパク質分解と切断を活性化し、アポトーシスを誘導する(56)。
Intrinsic (mitochondrial pathway) mechanisms involve the activation of mitochondria through intracellular damage such as DNA damage via chemoradiotherapy. Intracellular insults result in the p53 activation of the pro-apoptotic B-cell lymphoma 2 (Bcl-2) family (including Bax, Bid and Bad) that induce mitochondrial release of cytochrome c (Cyc-c) (58). Cyc-c is a key component, alongside procaspase 9 and apoptotic protease activating factor-1 (Apaf-1), that form an apoptosome, an apoptosis inducing complex (59). The apoptosome then converges alongside the extrinsic pathway in activating caspase-3.

Bcl-2 family members such as Bax, Bid and Bad are proapoptotic factors that target the mitochondrial membrane and facilitate Cyc-c release. However, Bcl-2 is permanently anchored to the mitochondrial wall, is anti-apoptotic and prevent the release of Cyc-c (55). Therefore, the Bcl-2 family work in homeostasis to regulate cellular death. In aggressive prostate cancer, Bcl-2 is upregulated, swinging the homeostatic balance firmly towards anti-apoptosis (60). This overexpression is seen in chemoradiotherapy-resistant prostate cancer phenotypes, therefore can be seen as a key indicator in the prognosis of aggressive prostate cancer (55, 60). Upstream of Bcl-2 family receptors, mutations of the p53 tumor suppressor gene are also characteristic of malignant prostate cancer and CRPC, further highlighting the critical role of apoptosis in pathogenicity (61). The true genetic and molecular pathophysiology of prostate cancer is a complex topic. Unlike breast cancer, there are no highly penetrant and dominating genetic mutations that account for the majority of prostate cancer cases. Thus, there is huge scope for future therapeutic innovation and bespoke genetic analysis may well play a role in reducing the prevalence of CRPC.
Bax、Bid、BadなどのBcl-2ファミリーメンバーは、ミトコンドリア膜を標的とし、Cyc-cの放出を促進するアポトーシス促進因子です。しかし、Bcl-2はミトコンドリア壁に恒久的に固定されており、抗アポトーシスであり、Cyc-cの放出を防止する(55)。したがって、Bcl-2ファミリーはホメオスタシス(恒常性)で細胞死を調節する働きをしている。侵攻性の前立腺癌では、Bcl-2がアップレギュレーションされ、恒常性バランスが抗アポトーシスに向かってしっかりと揺れ動く(60)。この過剰発現は化学放射線療法抵抗性前立腺癌の表現型に見られるので、侵攻性前立腺癌の予後における重要な指標と見なすことができる(55,60)。 Bcl-2ファミリー受容体の上流では、p53腫瘍抑制遺伝子の変異も悪性前立腺癌とCRPCに特徴的であり、病原性におけるアポトーシスの重要な役割をさらに強調している(61)。前立腺がんの真の遺伝的および分子的病態生理学は複雑なトピックです。乳がんとは異なり、前立腺がんの症例の大部分を占める浸透性が高く優勢な遺伝子変異はありません。したがって、将来の治療革新には大きな余地があり、オーダーメイドの遺伝子解析はCRPCの有病率を減らす役割を果たす可能性があります。


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  • Cdc6ノックダウンはTAMを形質転換
  • Cdc6ノックダウンはBcl2ファミリーの発現を活性化
  • Cdc6ノックダウンはP53を活性化
  • Cdc6ノックダウンはP16を活性化
  • P16 の活性化はRbがん抑制遺伝子を活性化
  • PTENはPI3K-AKT-mTOR経路を抑制する。細胞増殖シグナルの抑制
  • Klothoは、IGF受容体のチロシンキナーゼ受容体リン酸化の細胞増殖シグナルを抑制する
  • P53はがん細胞をアポトーシスさせるゲノムの守護神