Invasion and metastasis in cancer: molecular insights and therapeutic targets

Abstract

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Fig. 1

Historical progression in cancer metastasis research: from the discovery of important theoretical mechanisms to the application of clinical drugs. FDA food and drug administration

Fig. 2

Metastasis of cancer cells. Tumor cells with inherent genomic instability accumulate mutations leading to significant heterogeneity. Metastasis involves the colonization of distant sites by various clones from the primary tumor, resulting in polyclonal metastasis. Studies on various solid cancer metastasis patterns support this concept by revealing polyclonal seeding and heterogeneity within metastatic lesions. The bidirectional flow of cancer cells, as proposed by tumor self-/cross- seeding (indicated by green and orange arrows) or secondary metastasis from metastatic site (blue arrows), adds metastasis complexity, indicating potential intra- and interpatient heterogeneity in treatment response and resistance

Fig. 3

Mechanisms of the cancer metastasis cascade. At primary tumor sites, cancer-associated fibroblasts (CAFs) and stromal cells create a metastasis-conducive niche to support cancer cell EMT process, dissemination, and migration. As migrating cancer cells interact with circulating CAFs and myeloid cells to enhance survival and invasiveness while evading immune detection, they eventually reach the metastatic sites where they transition from dormancy and interact with the microenvironment to initiate active proliferation. The metastatic cascade initiated by primary tumor cells invading adjacent tissues via EMT is facilitated by CAFs that promote motility and ECM degradation. Moreover, macrophages and tumor-associated neutrophils (TANs) significantly contribute to ECM breakdown, facilitating cancer cell intravasation and survival in circulation by forming aggregates with platelets and myeloid cells to evade immune surveillance. Key interactions between cancer cells and the endothelium facilitate adhesion and extravasation into bone marrow, supported by the metabolic reprogramming of osteoblasts and osteoclasts. In addition, myeloid cells enhance cancer cell survival and metastasis through immune suppression, metabolic support, and ECM remodeling, including the crucial activities of neutrophils and macrophages in facilitating tumor cell adhesion, invasion, and metastatic proliferation at secondary sites

Fig. 4

Therapeutic strategies targeting cancer metastasis. These strategies range from directly and precisely attacking metastatic cancer cells to delicately modulating the intricate TME, and further encompass personalized treatment plans for specific organ metastases. Specifically, these strategies integrate chemotherapy, targeted therapy, immunotherapy, local therapy, and combined therapy to achieve precise elimination of cancer cells. Additionally, anti-angiogenic therapy, targeting the ECM and tumor-associated cells, and regulating tumor metabolic mechanisms indirectly impact the TME, ultimately providing a more precise therapeutic approach for cancer metastasis