A new hypothesis: some metastases are the result of inflammatory processes by adapted cells, especially adapted immune cells at sites of inflammation

• There is a hypothesis that metastasis is the result of cancer cell migration from the tumor extracellular matrix to the bloodstream or lymphatic vessels as circulating tumor cells (CTCs), and then to the new site. CTCs only use lymphatic routes to migrate to the nearby lymph nodes, but not for traveling long distances⁶. Cell migration occurs when tumor epithelial (E) cells lose their cell-cell adhesion and become motile mesenchymal (M) cells, i.e. epithelial-mesenchymal transition (EMT). When these CTCs exit the bloodstream, they undergo a reverse process called mesenchymal-epithelial transition (MET) to continue their differentiation and develop a secondary tumor^7–9.

In inflammatory breast cancer, there is a correlation between immune activation and CTCs with EMT characteristics¹⁰. Cohen et al. hypothesized that EMT could be the result of inflammatory processes initiated by activated immune cells¹⁰. Epithelial cells from the colonic epithelium of patients with benign colon diseases also circulate in the blood¹¹. During wound healing, epithelial cells migrate and disperse as individual mesenchymal cells by down regulating cell-cell junctions¹². Thus, CTCs in blood could be the result of inflammation.

• By querying published available data sets^13–17, we calculate the probability of not detecting any CTCs in blood from patients with metastatic breast cancer, and the result is 0.6. That means there might be other phenomena, beside CTCs, that cause metastasis. Since, no CTCs were detected in the blood of 29% of metastatic breast cancer patients starting a first or new line of therapy, it is unlikely that treatments are responsible for not observing CTCs in blood¹⁶.

• CTC-clusters are rare compared with single CTCs, however CTC-clusters, which usually include platelets and white blood cells¹⁸, significantly increase metastatic potential¹⁹. Moreover inhibition of platelet activation or platelet depletion decreases metastasis rates^20–22. There is a hypothesis that metastasis is reduced when the host is platelet depleted because platelets are protecting tumor cells from natural killing cells^23,24 Platelets in tumor cell clusters release transforming growth factor β (TGF-β)²⁵, and tumor cells that are bound to platelets highly express EMT-associated genes²⁶.

• Cancer of unknown primary origin (CUP) is defined by the presence of metastatic disease with no identified primary tumor. CUPs are 3.5% of all human malignancies, and one of the ten most frequent cancers worldwide²⁷. The major sites of CUP are bones, liver, lung, and lymph nodes²⁸, the sites where immune cells are most active.

• New studies show that recruited bone marrow progenitor cells change the host’s environment to generate the “pre-metastatic niche” to which the tumor cells metastasize²⁹. Bone marrow-derived haematopoietic progenitor cells (HPCs) that express vascular endothelial growth factor receptor 1 form cellular clusters at pre-metastatic sites before appearance of a single tumor cell³⁰.

• There is evidence of metastasis to the site of injury. Two patients with squamous cell carcinoma of the lung developed distant localized metastatic disease at sites of physical injuries; one to the knee injured in an accidental fall six weeks earlier, and the other to portions of the liver injured in a mechanical fall two months earlier³¹. In a mice model of metastatic breast cancer, radiation-induced pulmonary injury lead to chronic inflammatory responses, and development of pre-metastatic niches³². In another mice model, hepatic ischemia-reperfusion injury increased the number of liver metastases of human pancreatic cancer (Capan-1) cells, which were injected into the mice spleen³³. Several studies show that lung injury induced by the chemotherapy drug, bleomycin, increases lung metastases; they also observed tumor cell adherence to extracellular matrix and fibrin at injured areas^34,35. Therefore we suggest that the sites of injuries are potential metastatic sites.