Sambi Manpreet, Haq Sabah, Samuel Vanessa, Qorri Bessi, Haxho Fiona, Hill Kelli, Harless William, Szewczuk Myron R
Department of Biomedical and Medical Sciences, Queen's University, Kingston, ON, Canada.
Department of Biomedical and Medical Sciences, Queen's University, Kingston, ON, Canada; ENCYT Technologies, Inc., Membertou, NS, Canada.
Breast Cancer (Dove Med Press). 2017 Feb 28;9:85-93. doi: 10.2147/BCTT.S130838. eCollection 2017.
One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation.
开发针对恶性肿瘤的有效疗法的主要挑战之一是特异性靶向肿瘤内异质性癌细胞群体。癌性肿瘤由多种具有特定受体和蛋白质的不同细胞组成，这些受体和蛋白质可能是药物的潜在可行靶点。此外，来自局部微环境的各种信号也可能促进肿瘤生长和转移。总体而言，必须对这些因素进行战略性研究并加以靶向，以制定有效的治疗方案。需要对靶向多模态方法进行战略性研究，以制定出成功控制肿瘤生长和预防转移负担的治疗方案。特别是乳腺癌，由于可能出现的多种癌症亚型以及可以利用的多个药物靶点，呈现出独特的问题。例如，肿瘤分期和亚型通常决定合适的治疗方案。替代多模态疗法应考虑时间依赖性给药的重要性，以及靶向局部和全身肿瘤环境。许多综述和论文都简要提及了这种细胞异质性的临床意义；然而，对于反映这种多样性的研究模型的开发以及针对这些亚群的多模态疗法，讨论很少。在这里，我们总结了目前对乳腺癌亚型肿瘤内异质性起源的理解，及其对肿瘤进展、转移潜能和治疗方案的影响。我们还讨论了利用特定乳腺癌模型进行研究的优缺点，包括体外单层系统和三维乳腺球，以及可能能够涵盖这种异质性的体内小鼠模型。最后，我们总结了多靶点疗法开发方面的一些当前进展，这些疗法在单独使用或与传统手术、化疗和/或放疗方案联合使用时，在临床和临床前研究中已显示出有希望的结果。
